Osteoarthritis and Cartilage 31 (2023) 1437–1453

Osteoarthritis year in review 2023: metabolite and protein biomarkers

Ming Liu, Nafiza Haque, Jingyi Huang, Guangju Zhai
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Division of Biomedical Sciences (Genetics), Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Canada

a r t i c l e i n f o s u m m a r y

Article history: Objective: To highlight the advances over the past year in metabolite/protein biomarkers for osteoarthritis
Received 23 May 2023 (OA).
Accepted 14 August 2023 Method: A literature search of five databases including PubMed, Web of Science, Scopus, Ovid Medline, and
Embase was performed for studies on metabolite/protein/peptide/biochemical markers for OA published
Keywords: between April 1st, 2022 and March 31st, 2023. Records were then screened to include only original research
Osteoarthritis
articles using directly collected human specimens, in English language, and with full text available. Data
Biomarker
from eligible studies were systematically extracted and summarized.
Metabolite
Protein
Results: A total of 1600 unique records were extracted, out of which 46 fulfilled the inclusion criteria
and were used for data extraction. Forty-one of these 46 studies focused on biomarkers for OA/OA
severity/progression, four on OA clustering, and one on OA treatment outcomes. Twenty-nine studied
protein markers for OA, thirteen studied metabolite markers, and four studied both. While many
studies were the validation of the previously reported biomarkers, a number of novel metabolite/
protein biomarkers and biomarker panels were reported in the past year. Biomarker panels might be
useful to subset OA patients.
Conclusion: The number of studies on OA clustering is rising. Although validation in larger cohorts is needed
in order to utilize reported biomarkers in clinical practice, these discoveries help better understand the
pathogenesis of OA, provide insights into possible mechanisms underlying poor treatment outcomes, and
aid in developing personalized treatment based on OA subtypes.
© 2023 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).

Introduction the molecular alterations preceding the structural changes or

Osteoarthritis (OA) is a heterogeneous disorder characterized
by multi-tissue failure in diarthrodial joints, and has been pro­
posed to be a complex syndrome 1 and a whole person disease 2
due to its complexity as seen in the variable etiologies and
clinical presentation, discordance between structural signs and
symptoms, 3 and different responses to treatment,4 all of which
pose significant challenges for OA prevention, diagnosis, and
treatment development. Biomarkers are objective, quantifiable
characteristics of biological processes that can be measured re­
liability with sufficient precision and provide summary of bio­
logical, physiological, or pathological pathways associated with
the conditions examined.5,6 In the OA field, the only biomarkers
currently in use are the imaging markers which can not detect
provide therapeutic targets, thus, there is a pressing need for
meaningful diagnostic and prognostic biochemical markers that
can be easily measured and can help understand the pathogen­
esis of the disease and mechanisms underlying poor treatment
outcomes, and in the clinical setting, assist in early diagnosis,
prediction of disease progression, and stratification of patients
for clinical trials, which eventually aids in the development of
disease modifying OA drugs and precision medicine in OA. In this
review, we aimed to highlight the advances over the past year in
metabolite and protein biomarkers for OA risk and progression,
OA clustering, and OA treatment outcomes.
Methods

This review was conducted and reported in accordance with the

* Correspondence to: Division of Biomedical Sciences (Genetics), Faculty of Preferred Reporting Items for Systematic Review and Meta-
Medicine, Memorial University of Newfoundland, St. John’s A1B 3V6, Canada. Analyses7 (Supplementary Table 1).
E-mail address: guangju.zhai@med.mun.ca (G. Zhai).

https://doi.org/10.1016/j.joca.2023.08.005
1063-4584/© 2023 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1438 M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453
Database Search query
PubMed ((osteoarthriti*) AND ((biomarker*) OR (proteomic*) OR (metabolom*)
OR ((( marker*) OR (predict*) OR (associat*)) AND ((biochemical) OR
(metaboli*) OR (peptide*) OR (protein)))))
Web of Science TS=((osteoarthriti*) AND ((biomarker*) OR (proteomic*) OR
(metabolom*) OR (((marker*) OR (predict*) OR (associat*)) AND
((biochemical) OR (metaboli*) OR (peptide*) OR (protein)))))
Scopus (TITLE-ABS-KEY ((osteoarthriti*) AND ((biomarker*) OR (proteomic*) OR
(metabolom*) OR (((marker*) OR (predict*) OR (associat*)) AND
((biochemical) OR (metaboli*) OR (peptide*) OR (protein))))))
Ovid Medline (exp osteoarthritis/ OR osteoarthrit*.mp.) AND (exp proteomics/ OR exp
metabolomics/ OR exp biomarker/ OR (proteomic* OR metabolom* OR
biomarker*).mp. OR ((exp peptides/ OR (peptide* OR protein* OR
biochemical OR metaboli*).mp.) AND (marker* OR predict* OR
associat*).mp.))
Embase ((’osteoarthritis’/exp OR osteoarthriti*:ab,ti) AND (’proteomics’/exp OR
’metabolomics’/exp OR ’biomarker’/exp OR proteomic*:ab,ti OR
metabolom*:ab,ti OR biomarker*:ab,ti OR ((’peptides’/exp OR
peptide*:ab,ti OR protein*:ab,ti OR biochemical:ab,ti OR metaboli*:ab,ti)
AND (marker*:ab,ti OR predict*:ab,ti OR associat*:ab,ti))))
#
: Date of publication filter does not apply, hence records prior to April 1st, 2022 or after March 31st, 2023 were removed after literature search.
Table 1
Literature search queries and filters.
Search strategy
Five databases including PubMed, Web of Science, Scopus, Ovid
Medline, and Embase were searched for publications on OA metabolite/
protein biomarkers published between April 1st, 2022 and March 31st,
2023. The key phrases used for the search were: osteoarthritis/osteoar­
thritic+biomarker(s)/proteomic(s)/metabolomic(s)/metabolome; os­
teoarthritis/osteoarthritic+metabolism/metabolic/metabolite(s)/bio­
chemical/peptide(s)/protein+marker(s)/predictor(s)/predict(s/ed/ing/
ion)/associat(s/ed/ing/ion). The search queries and filters are presented
in Table 1.
Study selection
After the removal of duplicated records, abstract and full text
screening was conducted according to the following inclusion and
exclusion criteria:
• Inclusion criterion: original research article focusing on meta­
bolite/protein/peptide/biochemical biomarkers for OA in any
joint in human.
• Exclusion criteria: no full text; not in English; pure computa­
tional studies; review articles or meta-analyses; not population-
based study; not OA-focused; not metabolite/protein biomarker-
focused; biomarker level did not differ between controls and OA
patients examined; sample size < 10 in any study group without
an independent replication; data inconsistency throughout the
article (discrepancies between the results described in the text
and the results presented in the table and/or figure).
Study risk of bias assessment
The methodological quality of the included studies was assessed
using different tools according to study types (cross-sectional,
longitudinal, case-control),8–10 and OA clustering studies were
Filter/limit
English;
Full text;
Date of publication=April 1st, 2022-March 31st, 2023
English;
Document type=article/proceeding paper/early access;
Date of publication=April 1st, 2022-March 31st, 2023
English;
Document type=article/letter;
Subject=medicine/biochemistry, genetics and molecular biology/
immunology and microbiology/pharmacology, toxicology and
pharmaceutics/ health professions/ multidisciplinary;
Date of publication=April 1st, 2022-March 31st, 2023
English;
Full text;
Year of publication=2022–2023#
English;
Document type=article/article in press/conference paper/data paper/letter
/preprint;
Year of publication=2022–2023#
assessed using a narrative analysis11 (supplementary methods,
Supplementary Table 2).
Results
The aforementioned search strategy identified a total of 3421
records, out of which 1134 were from PubMed, 594 from Web of
Science, 738 from Scopus, 97 from Ovid Medline, and 858 from
Embase. After duplicate removal and abstract screening, full text of
the remaining 187 studies were accessed, and 141 studies were
further excluded based on the exclusion criteria. 46 studies were
included in this review. The detailed screening process is presented
in Fig. 1.
Study Characteristics
Characteristics of each study including article first author, the
approach(es) used to measure biomarker levels, phenotype(s) of
study group(s), sample size(s), disease joint(s), and sample type(s)
were extracted and summarized during full text review and are
presented in Table 2. Among the 46 studies, 34 studied OA in knee
joint, one studied hand, three studied temporomandibular joint
(TMJ), two studied spine, four studied multiple joints (knee, hip,
hand), and two did not specify joint studied. Blood sample was used
in 29 studies, blood and urine were used in five studies, synovial
fluid (SF)/synovial tissue (ST) was used in five studies, cartilage was
used in one study, and blood and SF/ST/cartilage were used in six
studies. The majority of the studies employed targeted approach
(n = 43), two studies applied untargeted approach, and one study
used both.
Risk of bias in studies
The quality assessment results are presented in Supplementary
results and Supplementary Table 3.
 M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453
Fig. 1
PRISMA flow diagram - search strategy and selection process of the included studies. PRISMA: Preferred Reporting Items for Systematic
Review and Meta-Analyses.
OA biomarkers
Forty-one out of these 46 articles studied metabolite/protein
biomarkers for OA/OA severity/progression, four studied biomarkers
for OA clustering, and one studied biomarkers for OA treatment
outcomes. Results for individual studies are present in Tables 3
and 4.
Discussion
Biomarkers for OA/OA severity/progression
Biomarkers for OA/OA severity/progression reported in the past
year mainly belong to at least one of the following categories: car­
tilage/bone structure/damage, inflammation, metabolism, or oxida­
tive stress markers. The majority of the identified biomarkers were
previously reported.
Cartilage/bone structure/damage biomarkers
Cartilage oligomeric matrix protein (COMP) is a large pentameric
glycoprotein that plays an important role in mediating the matrix
molecule interactions needed to organize the cartilage matrix.12
Findings from three new studies13–15 showed that serum COMP level
was higher in knee OA (KOA) than in controls and could distinguish
these two groups; it was positively associated with overall OA
burden and negatively associated with medial femorotibial com­
partment cartilage thickness at 4-year follow-up. Although some
evidence has shown that COMP has diagnostic and prognostic value
1439
as a biomarker for OA, these new studies all found a small effect size
and did not add much convincing evidence.
C-terminal cross-linked telopeptide of type II collagen (CTX-II) is
a byproduct of articular cartilage breakdown. Liem et al.16 found that
higher values of baseline urinary CTX-II were associated with an
increased risk of OA disease progression. Lu et al.17 reported that
serum CTX-II level was higher in traumatic KOA patients than in
controls, and higher in Kellgren and Lawrence (KL) grade III+IV than
in KL grade I+II patients. Studies on CTX-II as an OA biomarker have
consistently shown that urinary CTX-II had a potential to be a pro­
tein biomarker for OA and OA progression.18–20 The two new studies
provided further evidence, though the predictive power of this
protein needs to be evaluated in larger cohorts and within different
subgroups as the performance of this biomarker differs between
different age and sex groups and different populations.19–21 CTX-I
was reported in one study15 to be upregulated in KOA, had higher
levels in KL grade II than in KL grade I patients, and could distinguish
KOA patients from controls and between different severity groups.
This study had a small sample size and significantly different age and
sex distribution between groups, its findings need to be validated.
CTX-I was not as well studied in regard to its association with OA and
there has not been any strong evidence suggesting its potential as an
OA biomarker previously.
Cartilage acidic protein 1 (CRTAC1) was highlighted in four stu­
dies to be positively associated with OA risk, severity, and overall OA
burden, as well as a predictor for incident diagnosis and progression
of OA,13,22–24 but the effect sizes and predictive power for overall OA
burden, severity, and progression were all small. In a study with
 1440

Reference Approach Phenotype and sample size Joint Tissue type

Abou-Raya et al.43 Targeted Early KOA (n = 40), severe KOA (n = 10), non-OA (n = 40) Knee Serum
Amirkhizi et al.38 Targeted Vitamin-D-sufficient KOA(n = 60), vitamin-D-insufficient KOA (n = 64), non-OA (n = 65) Knee Serum
Angelini et al.74 Targeted KOA (n = 297) Knee Serum, urine
Cambon-Binder et al.59 Targeted Erosive hand OA (n = 168), non-erosive hand OA (n = 218); OA PIPs (n = 7), non-OA PIPs (n = 7); OA MCPs (n = 5), non-OA MCPs Hand Serum, cartilage
(n = 9)
Cheng et al.51 Targeted KOA of different disease severities (n = 50) Knee Plasma, SF
Chiba et al.54 Targeted KOA with CS (n = 48), KOA without CS (n = 249) Knee Serum
Costello et al.4 Targeted Discovery: KOA with sustained pain post TKR (n = 35), KOA without sustained pain post TKR (n = 323); replication: KOA with Knee Plasma
sustained pain post TKR (n = 118), KOA without sustained pain post TKR (n = 118)
Drvar et al.67 Targeted KOA (n = 40), non-OA (n = 40) Knee PBMCs
Elamir et al.27 Targeted KOA (n = 100), non-OA (n = 80) Knee Serum
Feng et al.34 Targeted DDw/oR with early-stage OA (n = 15), DDw/oR with late-stage OA (n = 13), DDw/oR without OA (n = 14) TMJ SF
Goode et al.75 Targeted Patients with different lumbar spine radiographic features with and without LBP (n = 731) Spine Serum, urine
Hunter et al.32 Targeted KOA with radiographic and pain progression (n = 194) and KOA with only radiographic or pain progression or no progression at 48 Knee Serum, urine
months (n = 406); KOA with radiographic progression (n = 297) and KOA without radiographic progression (n = 303) at 48 months
Hussain et al.15 Targeted KOA of different severities (n = 100), non-OA (n = 50) Knee Serum
Jitjumnong et al.60 Targeted LDD of different severities (n = 50), non-LDD (n = 50) Spine Plasma
Kamel et al.44 Targeted KOA (n = 70), non-OA (n = 30) Knee Serum, SF
Liang et al.65 Targeted OA (n = 206), non-OA (n = 60) Not specified Plasma
Liem et al.16 Targeted KOA with different radiographic or clinical features (n = 600) Knee Serum, urine
Loef et al.53 Targeted/ untargeted KOA and hand OA with different severities (n = 216) Knee, hand Plasma
Lu et al.17 Targeted KL grade I+II traumatic KOA (n = 87), KL grade III+IV traumatic KOA (n = 83), non-OA (n = 80) Knee Serum
Nemet et al.57 Targeted KOA (n = 25), non-OA (n = 19) Knee Blood
Papaneophytou et al.33 Targeted Early OA (n = 44), late OA of different severities (n = 130), overweight non-OA (n = 38) Knee Serum
Perruccio et al.42 Targeted OA (n = 3049), non-OA (n = 3049); female OA (n = 1702), male OA (n = 1348); multisite OA (n = 25), single-site OA (n = 3024) knees, hips, hands Serum
Rifal et al.41 Targeted KOA of different severities with hyperuricemia (n = 38), KOA of different severities with normal uric acid levels (n = 36) Knee Serum
Rockel et al.76 Targeted KOA (n = 214) Knee Plasma
Rong et al.66 Targeted KOA (n = 41), meniscal injury patients (n = 20) Knee Synovium, SF
Sarkar et al.62 Untargeted KOA (n = 60), non-OA (n = 40) Knee Plasma, SF
Sasaki et al.70 Targeted KOA with different KL grades and synovitis scores (n = 597) Knee Plasma, serum
Selim et al.58 Targeted KOA (n = 40), non-OA (n = 20) Knee Serum
Shao et al.46 Targeted TMJOA (n = 30), TMJID (n = 30) TMJ SF
Shekhar et al.61 Targeted KOA (n = 49), non-OA (n = 49) Knee Serum, SF
Singh et al.14 Targeted Participants with data on MRI imaging markers and biochemical markers (n = 119 and 155 for baseline, n = 127 and 129 for Knee Serum
follow-up)
Singh et al.26 Targeted KOA (n = 80), non-OA (n = 80) Knee Serum
M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453

Sodhi et al.52 Targeted KOA with different synovial vascular pathology features (n = 97) Knee SF
Styrkarsdottir et al.22 Targeted Knee/hip/hand OA (n = 3330), non-OA (n = 50,935); incident knee/hip/hand OA (n = 6619) and non-OA during follow-up Knee, hip Plasma
(n = 44,316); knee/hip OA who progressed to having TJR (n = 607), knee/hip OA who did not progress to having TJR (n = 671)
Szilagyi et al.13 Targeted OA (n = 426), non-OA (n = 1847); OA of different severities (n = 3103); KOA progressor (n = 198) and non-progressor (n = 1767); HOA Knee, hip, hand Plasma
progressor (n = 127) and non-progressor (n = 1871)
23
Tardif et al. Untargeted Discovery: obese KOA (n = 10), non-obese KOA (n = 10), non-OA (n = 8); replication: obese OA (n = 10), non-obese KOA (n = 10), non- Knee Serum, plasma
OA (n = 20)
37
Torga et al. Targeted KOA of different OARSI grades (n = 20) Knee Cartilage
Trajerova et al.50 Targeted KOA patients with improved, unchanged, and worsened clinical trajectories (n = 119) Knee SF
Tudorachi et al.56 Targeted Mild KOA (n = 39), severe KOA (n = 17), non-OA (n = 29) Knee Blood
Ukibe et al.40 Targeted Premenopausal/HIV/OA (n = 25), premenopausal/HIV/non-OA (n = 21), postmenopausal/HIV/OA (n = 21), postmenopausal/HIV/ Not specified Serum
non-OA (n = 21)
Ungsudechachai et al.45 Targeted KOA without synovitis (n = 16), KOA with low-grade synovitis (n = 19), KOA with high-grade synovitis (n = 15) Knee Plasma, ST, SF
Watanabe et al.35 Targeted DJD-TMJ (n = 17), non-DJD-TMJ (n = 17); younger DJD-TMJ (n = 10) and non-DJD-TMJ (n = 11); older DJD-TMJ (n = 7) and non-DJD- TMJ Serum, urine
TMJ (n = 6)
Xie et al.68 Targeted Participants with different rates of cartilage volume reduction (n = 344) Knee Serum
Zertuche et al.69 Targeted Incident radiographic OA (n = 258), non-OA (n = 516); incident symptomatic OA (n = 260), non-OA (n = 518) Knee Plasma
Zheng et al.55 Targeted Participants who developed OA at 5-year follow-up (n = 1089), non-OA at 5-year follow-up (n = 9641) Knee Plasma, whole blood
(continued on next page)
 M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453 1441

small sample sizes, CRTAC1 was found to be the most significant

peripheral blood mononuclear cells; SF: synovial fluid; ST: synovial tissue; TMJ: temporomandibular joint; TJR: total joint replacement; TMJID: temporomandibular joint internal derangement; TMJOA: temporomandibular joint
CS: central sensitization; DDw/oR: disc displacement without reduction; DJD-TMJ: degenerative joint disease of the temporomandibular joints; HIV: human immunodeficiency virus; HOA: hip osteoarthritis; JSL: joint space loss;
KL: Kellgren and Lawrence; KOA: knee osteoarthritis; LBP: lower back pain; LDD: lumbar disc degeneration; MRI: magnetic resonance imaging; OA: osteoarthritis; OARSI: osteoarthritis research society international; PBMC:
contributor among a set of 9 proteins discriminating OA from con­
trols.29 CRTAC1 is a glycosylated extracellular matrix protein that
was initially identified as a marker of chondrocyte development
Tissue type

from mesenchymal stem cells.25 CRTAC1 as a potential OA biomarker

was only discovered recently and relevant studies are very limited.
Serum

Extended research on this protein is much needed before it can be

utilized as an OA biomarker.
Matrix metallopeptidases (MMPs) are also proteins playing im­
portant roles in cartilage integrity. Three studies focused on MMP-3
in KOA14,26,27 and found that serum MMP-3 level was higher in KOA
especially in patients of higher KL grades, could distinguish between
Discovery: KOA JSL and pain progressor (n = 192), composite comparator (JSL and pain non-progressor+JSL or pain progressor only, Knee
Joint

KOA and controls and different severity groups with moderate ac­
curacy. Its level was also positively correlated with Western Ontario
and McMaster Universities Osteoarthritis Index (WOMAC) score,
patellar cartilage volume loss and total bone area reduction after 4
n = 404); JSL progressor (n = 103), JSL and pain non-progressor (n = 199). Replication: KOA JSL progressor (n = 37), JSL non-

years. Levels of MMP-1 and -13 were also found to be higher in

KOA.34 MMPs are the major proteases involved in extracellular ma­
trix degradation,28 a process that plays a significant role in the pa­
thogenesis of OA. MMP-3 and -13 levels increase in response to axial
compression and degradation of cartilage matrix, MMP-3 then pro­
motes synovitis and synovitis promotes the expression of MMP-3 in
return, forming a vicious cycle in the progression of OA.29 MMP-13
preferentially digests type II collagen,28 the main component of
cartilage, also degrades the proteoglycan molecule aggrecan, giving
it a dual role in matrix destruction,30 therefore, it is thought to be
the most important MMP in OA pathogenesis and an attractive
target for inhibitor development in the treatment of OA. MMP-1
protein expression in OA is not well studied in humans, but there has
been evidence that MMP-1 level is upregulated in SF of OA pa­
tients.31 The three new studies validated that MMPs have potential
to be OA biomarkers.
A number of other previously discovered cartilage/bone struc­
ture/damage biomarkers were also reported in the past year in­
cluding N-telopeptide of type I collagen (NTX-I), procollagen type II
C-terminal propeptide (PIICP), C-C chemokine receptor type 5
(CCL5), cartilage intermediate layer protein 2 (CLIP-2), and vitamin
D. Hunter et al.32 reported that adding baseline serum NTX-I or
change of urine NTX-I level over 24 months to respective imaging
marker models slightly increased the predictive power for OA
radiographic and pain progression over 48 months. Papaneophytou
et al.33 found that serum PIICP level was decreased in late OA and
Phenotype and sample size

negatively correlated with OA severity and knee pain, and can dis­
criminate late OA patients from overweight individuals without OA.
In two studies on temporomandibular joint OA (TMJOA),34,35 SF CCL5
progressor (n = 49)

level was found to be increased in TMJ disc displacement without

reduction (DDw/oR) patients with early-stage OA than in patients
without OA or with late-stage OA, and can distinguish DDw/oR pa­
tients with early-stage OA from other DDw/oR patients. Serum CCL5
level was also higher in female patients with degenerative joint
disease of the TMJ (DJD-TMJ) than in female controls, and was po­
Characteristics of the included studies.

sitively associated with bone metabolism rate, especially in rela­

osteoarthritis; TKR: total knee replacement.

tively young DJD-TMJ patients without other systemic symptoms,

and this level could distinguish DJD-TMJ from non-DJD-TMJ in fe­
Approach

Targeted

males. However, the diagnostic performance of this protein in male

patients needs further investigation. CCL5 is a chemokine that plays
a role in the recruitment of T helper cells to the affected joint to help
trigger inflammation processes via the release of pro-inflammatory
cytokines.36 The results of these two studies suggested that serum or
Table 2 (continued)

SF CCL5 level has the potential to be a biomarker for early detection

Zhou et al.24

of TMJOA especially in younger patients. Torga et al.37 reported that

Table 2
Reference

in end-stage KOA patients, the immunohistochemistry staining in­

tensity of CILP-2 in cartilage was positively associated with Os­
teoarthritis Research Society International (OARSI) grading. Again,
the main drawback of these studies are the small sample sizes.
 1442

Reference # of markers Identified Biomarker (s) Findings Estimates Biomarker Biomarker

tested application type
(identified)

Abou-Raya et al.43 2 (1) IL-8 Serum IL-8 ↑ in early KOA than in controls. OA vs. controls: 162.90 ± 145.50 vs. OA stage Protein
139.15 ± 39.64, p = 0.027.
Amirkhizi et al.38 1 (1) Vitamin D Vitamin D ↓ in KOA with insufficient Vitamin D OA vs. controls: 19.7 ± 5.5 vs. 42.7 ± 9.6 ng/ml, OA/OA severity Metabolite
and inversely correlated with inflammatory p < 0.0001. Correlation with IL-1β, TNF-α, and
factors. WOMAC scores ↑ in KOA with vitamin D hs-CRP: β = −0.51, −0.44, −0.50, all p < 0.0001.
insufficiency. WOMAC: p ≤ 0.011.
Angelini et al.74 16 (16) Combination of serum C2M, C3M, COMP, Three OA clusters: C1: low tissue turnover; F1 scores: discovery cohort: C1: 0.85, C2: 0.91, OA clustering Protein +
CRPM, ARGS, C10C, COLL2_1, COLL2_1NO2, C2: structural damage; C3: systemic C3: 0.88; validation cohort: no data. Metabolite
CTXI, hyaluronic acid, hsCRP, PRO_C2, NMID, inflammation. Validated in an external cohort.
RE_C1M, urine CTXI_ALPHA and CTXII.
Cambon-Binder 2 (1) CML Serum CML ↓ in erosive than in non-erosive Erosive vs. non-erosive hand OA: 178.7 OA/OA severity Metabolite
et al.59 hand OA. Cartilage CML ↑ in hand OA than in (157.1–208.8) vs. 194.7 (168.9–217.1) μmol/mol
non-OA. lysine, p = 0.01. OA vs. non-OA: 7 vs. 4 mmol/mol
lysine, p = 0.01.
Cheng et al.51 2 (2) C3-α and C3-β SF C3-α and C3-β levels were correlated with Correlation with severity: r = 0.39 and 0.47, both OA severity Protein
KOA severity and ↑ in OARSI grade ≥ 6 group. p < 0.01. SF level in OARSI ≥6 vs. < 6 groups:
C3-α: 1131 ± 69 vs. 939 ± 47 unit/ml; C3-β:
1011 ± 63 vs. 783 ± 51 unit/ml; both p < 0.05.
Chiba et al.54 1 (1) Glucose In KOA patients with CS, glucose was Association with KOOS pain: β = −0.448 OA severity Metabolite
negatively associated with changes in KOOS (−0.737,−0.158); p = 0.003; ADLs: β = −0.438
pain, ADLs, and sports scores from baseline to (−0.713, −0.163); p = 0.003; sports scores:
1-year follow-up. β = −0.706 (−1.21, −0.202); p = 0.007.
Costello et al.4 18,769 (4) PC aa C28:1, PC aa C32:0/PC aa C28:1, PC aa Plasma PC aa C28:1 and PC aa C28:1/PC aa PC aa C28:1: OR=0.66 (0.52–0.82); PC aa OA treatment Metabolite
C28:1/PC aa C32:0, and C14:2/SM C20:2 C32:0 were negatively associated with C28:1/PC aa C32:0: OR=0.6 (0.48–0.76); PC aa outcome
sustained pain after TKR, PC aa C32:0/PC aa C32:0/PC aa C28:1: OR=1.59 (1.29–1.96);
C28:1 and C14:2/SM C20:2 were positively C14:2/SM C20:2: OR=1.59 (1.29–1.96).
associated.
Drvar et al.67 1 (1) GNLY In female, GNLY labeling in PBL ↑ in OA than in OA vs. controls: p = 1 × 10-6. OA Protein
controls.
Elamir et al.27 3 (3) MMP-1, MMP-3, MMP-13 Serum MMP-1, MMP-3, and MMP-13 ↑ in KOA OA vs. controls: MMP-1: 2.89 ± 0.01 vs. OA Protein
than in controls and could diagnose OA. 1.15 ± 0.04; MMP-3: 2.37 ± 0.07 vs. 0.79 ± 0.01;
MMP-13:2.56 ± 0.02 vs. 1.02 ± 0.08; all p < 0.01.
Diagnostic performance: 100% specificity and a
sensitivity of 98%, 100%, and 100%, respectively,
M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453

from a model fit, no AUC data.

Feng et al.34 1 (1) RANTES (CCL5) RANTES ↑ in DDw/oR with early-stage TMJOA, DDw/oR with early-stage TMJOA vs. other DDw/oR OA stage Protein
can distinguish these patients from other patients: p < 0.05. AUC=0.798, from a model fit, no
DDw/oR patients. sensitivity/specificity data.
Goode et al.75 12 (10) Combination of N-cadherin, lumican, CTX-II, Three OA clusters: C1: degenerative changes; Variance explained by the principal OA clustering Protein +
OPG, RANTES, IL-6, CXCL6, hyaluronic acid, C2: ↓ biomarkers, pain, and degenerative components=48%, CCC=7.76. Metabolite
NPY, BDNF changes; C3: degenerative changes and
inflammation with pain.
Hunter et al.32 1 (1) NTX-1 For baseline and 24-month change in Imaging+NTX-1 vs. imaging: baseline markers: OA progression Protein
markers, adding NTX-I to imaging marker AUC=0.671 vs. 0.669; 24-month change in markers:
model increased the power for predicting AUC=0.724 vs. 0.713, from individual model fit.
progression.
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Table 3 (continued)

Reference # of markers Identified Biomarker (s) Findings Estimates Biomarker Biomarker

tested application type
(identified)

Hussain et al.15 2 (2) COMP, CTX-I Serum COMP and CTX-I ↑ in KOA than in
controls, and could distinguish KOA from
controls.
Jitjumnong et al.60 2 (2) MDA, 8-OHdG Plasma MDA and 8-OHdG ↑ in LDD than in
controls, and positively correlated with LDD
severity.
Kamel et al.44 1 (1) IL-17A In KOA, serum IL-17A ↑ than in controls and
positively correlated with SF IL-17A. Both IL-
17A levels positively correlated with VAS,
WOMAC scores, Lequesne scores, and
Lequesne index. SF IL-17A positively
correlated with KL grade and OA duration.
Liang et al.65 2 (1) mCRP Plasma mCRP level ↑ in OA than in controls,
and ↑ in KL grade IV than in KL grade III KOA,
can discriminate OA from controls.
Liem et al.16 13 (3) CTX-II Baseline uCTXII was associated with KL grade,
medial JSN, lateral osteophytes, joint space
width, and WOMAC pain scores.
Loef et al.53 631 (5) Fatty acids 20:4, 16:1, 18:1, 18:2, 22:5 KOA and hand OA were associated with the
lipidomic fraction of bound and free FA 20:4,
bound FA 16:1, FA 18:1, FA 18:2, and FA 22:5.
Lu et al.17 3 (3) TLR4, CXCL12, CTX-II Serum TLR4, CXCL12, and CTX-II ↑ in
traumatic KOA than in controls, and ↑ in KL
grade III+IV than in KL grade I+II group.
OA vs. controls: COMP: 17.38 ± 4.99 vs. OA/OA severity Protein
1.16 ± 0.39 U/L; CTX-I: 4.59 ± 1.69 ng/ml vs.
0.35 ± 0.14 ng/ml; both p = 0.001. AUC=1,
specificity=100%, sensitivity=99% and 100%,
respectively, p = 0.001 and 0.02, respectively,
from individual model fit.
LDD vs. controls: MDA: p = 0.01; 8-OHdG: 179.28 OA/OA severity Metabolite
(101.88–247.55) vs. 115.76 (77.12–164.79) ng/L,
p = 0.002. Correlation with severity: MDA: r = 0.49,
p = 0.001; 8-OHdG: r = 0.60, p < 0.001.
OA vs. controls: 11.6 ± 1.6 vs. 10.5 ± 1.9 pg/ml, OA/OA severity Protein
p < 0.05. Correlation between serum and SF IL-
17A: r = 0.34, p = 0.04. Correlation with disease
parameters: serum: r: 0.35–0.42, p: 0.01–0.02;
SF: r: 0.78–0.92, p < 0.001; KL grade: r = 0.93,
p < 0.001; OA duration: r = 0.66, p < 0.001.
OA vs. controls: 12.51 (7.78–24.81) vs. 5.04 OA/OA severity Protein
(3.45–9.77) ng/ml, p = 3.72x10-5; KL grade IV vs.
III: p < 0.05. AUC=0.76, from a model fit, no
sensitivity/specificity data.
KL grade: OR=1.15 (1.03–1.28); medial JSN: OA progression Protein
OR=1.06 (1.02–1.1); lateral osteophytes: OR=1.05
(1.01–1.1); joint space width: β = −0.005
(−0.008,−0.001); WOMAC pain scores: OR=1.02
(1.01–1.04).
Radiographic KOA: R2lipidomics = 0.03; radiographic OA severity Metabolite
hand OA: R2lipidomics = 0.02; hand function:
R2lipidomics = 0.06; hand pain: R2lipidomics = 0.12.
OA vs. controls: TLR4: 13.87 ± 1.99 vs. OA/OA severity Protein
9.01 ± 2.21 ng/ml; CXCL12: 9.27 ± 1.47 vs.
3.9 ± 0.96 ng/ml; CTX-II: 707.67 ± 119.17 vs.
341.18 ± 84.44 ng/L; all p < 0.001; KL III+IV vs. I+II
group: TLR4: 15.21 ± 1.54 vs. 12.58 ± 1.45 ng/ml;
CXCL12: 10.38 ± 1.05 vs. 8.21 ± 0.94 ng/ml, CTX-II:
801.45 ± 81.04 vs. 618.20 ± 71.12 ng/L; all
M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453

p < 0.001.
Nemet et al.57 5 (2) TC, LDL-C Prevalence of high TC and high LDL-C ↑ in OA vs. controls: high TC: 92% vs. 63.2%, p = 0.019; OA Metabolite
female KOA patients than in female controls. high LDL-C: 72% vs. 15.8%, p = 0.000.
Papaneophytou 3 (1) PIICP sPIICP ↓ in mild and severe LOA and negatively Mild-LOA:179.1 (148.4–278.9) pg/ml, severe-LOA: OA/OA severity Protein
et al.33 correlated with OA severity and knee pain at 177.6 (109.1–273.3) pg/ml, control: 703.4
rest and during walking, can discriminate LOA (593.0–922.8) pg/ml, p < 0.0001. Correlation:
from controls. severity: r = −0.68; pain: r = −0.44 for resting and
−0.42 for walking; all p < 0.0001. AUC=0.98
(0.945–0.995), sensitivity=96.2%, specificity=92.1%,
p < 0.0001, from a model fit.
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1443
Table 3 (continued) 1444

Reference # of markers Identified Biomarker (s) Findings Estimates Biomarker Biomarker

tested application type
(identified)

Perruccio et al.42 5 (2) HbA1c, hsCRP Percentage of individuals with hsCRP and OA vs. controls: hsCRP: 66.4% vs. 61.9%; HbA1c: OA/OA severity Protein
HbA1c levels within published threshold for 22.5% vs. 17.7%, both p ≤ 0.001; multisite vs. single-
moderate/elevated CVD risk ↑ in OA and site OA: hsCRP: 72.1% vs. 64.5%; HbA1c: 25.2% vs.
multisite OA, with hsCRP being predominant 21.7%, both p < 0.05. Female OA with high hsCRP:
in women and HbA1c being predominant 68.6%, male OA with high HbA1c: 26.4%.
in men.
Rifal et al.41 1 (1) Uric acid Hyperuricemia group had ↑ percentage of Severe OA in hyperuricemia vs. normal uric OA severity Metabolite
severe KOA compared to normal uric acid acid group: 60.5% vs. 22.2%, p = 0.002.
group, had a ↑ risk of severe KOA. OR=5.36 (1.93–14.84).
Rockel et al.76 151 (24) Combination of C0, tyrosine, threonine, Two KOA clusters were identified based on AUC=0.921 (0.846–0.965), p < 0.0001, no OA clustering Metabolite
histidine, lysine, taurine, leucine, valine, profiles of 24 metabolites. sensitivity/specificity data, used internal
citurlline, spermidine, LPC 14:0, PC aa C36:0, validation, mean predicted accuracy=85.1%.
36:6, 40:1, 42:0, 42:2, PC ae C38:6, 42:0,
42:2, 42:3, 42:5, 44:3, 44:6, SM C24:0
Rong et al.66 1 (1) TDO2 In OA, synovium TDO2 ↑ and positively OA vs. controls: t = −4.78, p = 0.009. Correlation OA/OA severity Protein
correlated with IL-1β, TNF-α, and KL grades, with IL-1β: r = 0.367, p = 0.018; TNF-α: r = 0.519,
can discriminate OA from controls. p < 0.001; KL grades: r = 0.521, p < 0.001.
AUC=0.80 (0.689–0.911), sensitivity=63.4%,
specificity=85%, from a model fit.
Sarkar et al.62 192 (1) LRG1 Plasma LRG1 ↑ in OA patients than in controls, OA vs. controls: fold increase > 1.66, p ≤ 0.0001. OA Protein
↑ in TKR than in UKR. TKR vs. UKR: fold increase=1.66, p = 0.015.
Sasaki et al.70 82 (1) Cystine Cystine was associated with OA severity, Correlation: severity: r = 0.397, p < 0.001, OA severity Metabolite
effusion-synovitis, and radiographic OA. q < 0.001, effusion-synovitis: r = 0.151, p = 0.009,
q = 0.375. Low vs. high effusion-synovitis groups:
p = 0.039, q = 0.587. Association with radiographic
OA: AUC=0.714 (0.667, 0.761), p < 0.001,
from a model fit; OR=3.7.
Selim et al.58 1 (1) Adropin Serum adropin ↓ in KOA than in controls and ↓ OA vs. controls: 46.3 ± 27.9 vs. 76.5 ± 27.2 pg/ml, OA/OA severity Protein
in female than in male OA, negatively p < 0.0001; female vs. male OA: 40.2 ± 17.7 vs.
correlated with KL grading, could distinguish 75.2 ± 47.2 pg/ml, p = 0.0016. Correlation with KL
between KOA and controls. grades: r = −0.54, p = 0.0003. AUC=0.85,
sensitivity=80%, specificity=90%, p < 0.001, from a
model fit.
Shao et al.46 6 (1) HMGB1 SF HMGB1 ↑ in TMJOA than in TMJID, TMJOA vs. TMJID: p < 0.05. Correlation: VAS: OA/OA severity Protein
positively correlated with VAS, JFLS-8, and r = 0.5512, p = 0.0016; JFLS-8: r = 0.4684,
M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453

radiographic stage, could distinguish TMJID p = 0.0054; OA stage: r = 0.4923, p = 0.0057.

from TMJOA patients.
Shekhar et al.61 1 (1) MMP-17 Serum MMP-17 ↑ in OA than in controls and ↑
with disease severity, can distinguish OA from
controls. Serum and SF MMP-17 were
associated with ↑ risk for advanced KOA.
Singh et al.14 3 (2) COMP, MMP-3 Serum COMP was negatively associated with
medial femorotibial compartment cartilage
thickness, and MMP-3 was negatively
associated with patellar cartilage volume and
total bone area after 4 years.
AUC= 0.8344 (0.7186–0.9503), Youden’s
Index= 0.7667, p < 0.0001, from a model fit.
OA vs. controls: 15.43 ± 0.91 vs. OA/OA severity Protein
14.71 ± 1.04 ng/ml, p < 0.001. KL grade IV vs. III
vs. II: serum: 16.06 ± 0.7 vs. 15.58 ± 0.27 vs.
14.76 ± 0.81 ng/ml, p < 0.001; SF: 5.96 ± 2.93
vs. 3.5 ± 1.79 vs. 2.3 ± 1.54 ng/ml, p = 0.001.
AUC=0.743 (0.646–0.841), sensitivity=75.5%,
specificity=71.4%, from a model fit. Association
with advanced KOA: serum: OR=11.333
(2.209–58.147), p = 0.004; SF: OR=27.556
(3.031–250.524), p = 0.003.
COMP for cartilage thickness: β = −0.070 mm OA severity/ Protein
(−0.138,−0.001), p = 0.045. MMP-3 for cartilage progression
volume: β = −141.548 mm3 (−254.917,−28.179),
p = 0.015; bone area: β = −0.729 mm2
(−1.340,−0.118), p = 0.02.
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Table 3 (continued)
Reference # of markers Identified Biomarker (s) Findings
tested
(identified)
Singh et al.26 1 (1) MMP-3 Serum MMP-3 ↑ in OA than in controls, and
positively correlated with KL grades, could
distinguish between OA and control and
different KL grades.
Sodhi et al.52 6 (1) C5 Among OA patients, ↑ SF C5 level was
associated with ↓ vascularization scores in
males. SF sC5b-C9 level ↑ in males than in
females, and ↑ in males with high SF C5.
Styrkarsdottir et al.22 1462 (3) CRTAC1, ACAN, NCAN CRTAC1 was positively associated with
prevalent OA, predicted incident OA diagnosis
and progression to joint replacement.
Individuals in the highest quintile of risk
based on CRTAC1 level, age, sex, and BMI had
a 9.8-fold risk of knee or hip OA. Adding ACAN
and NCAN to the model improved the
prediction of OA.
Szilagyi et al.13 171 (1) CRTAC1 CRTAC1 was positively associated with
overall OA burden, hand OA and KOA
severity and KOA progression.
Tardif et al.23 279 (4) CRTAC1, FBN1, VDBP, SERPINF1 A set of 9 proteins could discriminate OA from
controls with CRTAC1 being the most
significant contributor and ↑ in OA than in
controls. FBN1, VDBP, SERPINF1 all ↑ in OA
than in controls in the validation cohort.
Torga et al.37 2 (1) CILP-2 CILP-2 IHC staining intensity was positively
associated with OARSI grading.
Estimates Biomarker Biomarker
application type
OA vs. controls: 59.85 ± 39.92 vs. OA/OA severity Protein
14.52 ± 6.09 ng/ml, p = 0.0001. Correlation with
KL grades: r = 0.68, p = 0.000. OA vs. controls:
AUC=73.04% (0.775–0.904), specificity 71.25%,
sensitivity 77.5%, p = 0.000; KL grade I vs. II:
AUC=70.69% (0.681–0.922), sensitivity 72.41%,
specificity 70.00%, p = 0.000; KL grade II vs. III:
AUC=54.42% (0.569–0.851), Specificity 44.83%,
Sensitivity 78.26%, p = 0.009; KL grade III vs.
IV: AUC=74.22% (0.524–0.991), specificity
73.91%, sensitivity 75%, p = 0.032; all from
individual model fit.
Vascularization score in males: β = −0.005 (−0.009, OA severity Protein
−0.0001) per 1 ng/ml C5 change, p = 0.04. sC5b-C9:
male vs. female: p < 0.05; in males, high vs. low SF
C5: p < 0.05.
CRTAC1: KOA: OR=1.34 (1.27–1.41), p = 5.5 × 10-29, OA/OA Protein
HOA: OR=1.19 (1.11–1.28), p = 2.1 × 10-6, predict progression
KOA: HR=1.40 (1.35–1.46), p = 1.08 × 10-69, predict
HOA: HR=1.25 (1.19–1.31), p = 2.61 × 10-19,
progression to knee replacement: HR= 1.20
(1.08–1.33), p = 5.2 × 10-4, hip replacement:
HR= 1.22 (1.08–1.38), p = 1.4 × 10-3. CRTAC1 vs.
CRTAC1+ACAN+NCAN model: AUCprevalent
KOA= 0.736 (0.724–0.749) vs. 0.742 (0.729–0.754),
AUCprevalent HOA= 0.738 (0.722–0.754) vs. 0.749
(0.733–0.765), AUCincident KOA= 0.718 (0.712–0.724)
vs. 0.722 (0.716–0.728), AUCincident HOA= 0.696
(0.689–0.703) vs. 0.705 (0.698–0.712). All from
individual model fit.
Overall OA: β = 0.09 (0.06–0.12), p = 3 × 10-8; hand OA/OA severity/ Protein
OA severity: β = 0.03 (0.01–0.04), p = 1 × 10-3; KOA progression
severity: β = 0.05 (0.03–0.07), p = 3 × 10-6; KOA
progression: β = 0.25 (0.09–0.41), p = 2 × 10-3.
OA vs. controls: AUC > 95%, from a model fit. OA Protein
M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453
CRTAC1: OA-obese vs. controls: p = 0.007,
OA-non-obese vs. controls: p = 0.003. Protein
validation: FBN1: p = 0.044, VDPB: p = 0.022,
SERPINF1: p = 0.064.
Rho = 0.436, p = 0.005. OA severity Protein
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1445
Table 3 (continued) 1446

Reference # of markers Identified Biomarker (s) Findings Estimates Biomarker Biomarker

tested application type
(identified)

Trajerova et al.50 20 (3) CXCR4, CCR7, CXCL10 Low CXCR4 and CCR7 expression on Improved vs. worsened: Subset 1 (high expression OA clustering Protein
macrophages and high CXCL10 in SF were of CXCR4 and CCR7): 86.1% vs 95.5%; p = 0.009;
linked to improved clinical trajectory. Subset 2 and 3 (low expression of CXCR4 and
CCR7): 4.72% vs 1.70%; p = 0.024, 4.48% vs 0.24%;
p = 0.005. Improved vs. unchanged: Subset 1: 86.1%
vs 96.9%; p = 0.025; Subset 2: 4.72% vs 1.35%,
p = 0.042. CXCL10: improved vs. worsened: 339
(104–575) vs. 222 (2.96–441) pg/ml, unchanged vs.
worsened: 378 (115–640) vs. 222 (2.96–441) pg/
ml, both p = 0.002.
Tudorachi et al.56 5 (4) Glucose, TGs, LDL-C, and TC LDL, TC, TGs, and glucose ↑ in OA than in Severe OA vs. controls: TC: 207 vs. 193 mg/dl, OA/OA severity Metabolite
controls. Glucose level was associated with p = 0.026; OA vs. controls: TGs: 126 vs. 89 mg/dl,
KOA risk. p = 0.005; glucose: 105 vs. 97 mg/dl. LDL: ANOVA
p = 0.0427; glucose and KOA risk: OR=1.017
(1.001–1.035), p = 0.042.
Ukibe et al.40 2 (2) hsCRP, uric acid In premenopausal group, serum uric acid ↑ in Premenopausal OA vs. controls: uric acid: OA Protein +
OA than in non-OA. In postmenopausal group, 353.24 ± 67.15 vs. 256.76 ± 42.87, t = 5.68, p = 0.00. Metabolite
serum CRP and uric acid ↑ in OA than in Postmenopausal OA vs. controls: uric acid:
non-OA. 332.67 ± 73.15 vs. 261.62 ± 42.32, t = 3.85,
p = 0.00; CRP: 0.16 ± 0.09 vs. 0.03 ± 0.02, t = 6.03,
p = 0.00.
Ungsudechachai 1 (1) CLU In KOA, ST CLU ↑ in patients with synovitis ST CLU: data not reported. Plasma and SF CLU: OA severity Protein
et al.45 than in those without; plasma and SF CLU ↑ in high- vs. low-grade synovitis: p < 0.05 and
high-grade synovitis than in low-grade or no p < 0.01; high-grade vs. no synovitis: both
synovitis group and positively associated with p < 0.001; association with synovitis severity:
synovitis severity. plasma: rho = 0.56, p < 0.001, β = 0.004
(0.001–0.007), p = 0.017; SF: rho= 0.75, p < 0.001,
β = 0.005 (0.003–0.006), p < 0.001.
Watanabe et al.35 12 (1) CCL5 Serum CCL5 ↑ in DJD-TMJ than in controls, DJD-TMJ vs. controls: p < 0.05. Correlation with OA Protein
positively associated with bone metabolism bone metabolism markers NTX, CTX, BAP: DJD-TMJ
rate, especially in young DJD-TMJ subjects, group: r = 0.14, 0.52, 0.38; young DJD-TMJ: r = 0.41,
could distinguish DJD-TMJ from controls. 0.64, 0.64; controls: r = −0.56, 0.01, −0.28.
AUC=0.7093 (0.5172–0.9015), p = 0.0372, from a
model fit.
Xie et al.68 16,641 (2) C16:1/C14, C16:1/C12 C16:1/C14 and C16:1/C12 were associated Percentage of cartilage volume loss/year: C16:1/ OA progression Metabolite
M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453

with patellar cartilage volume change. C14: β = −0.12 (−0.10, −0.14), p = 8.80 × 10−7, C16:1/
C12: β = −0.12 (−0.10, −0.14), p = 2.66 × 10−6.
Zertuche et al.69 6 (1) AR Baseline AR was associated with a ↓ risk of RR (Q4 vs. Q1)=0.31 (0.15, 0.64). OA progression Metabolite
radiographic KOA at 30-month.
Zheng et al.55 3 (2) Glucose, HbA1c DM and poor glycemic control were Symptomatic KOA at 5-year follow-up: DM and OA Protein +
associated with symptomatic KOA at 5-year HbA1c≥7%: HR=1.41 (1.05–2.09), p = 0.036. Incident Metabolite
follow-up. ↑ HbA1c and glucose were symptomatic KOA was associated with
associated with ↑ risk of incident HbA1c > 7.7% and glucose > 186 mg/dl (HR > 1).
symptomatic KOA.
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Table 3 (continued)

Reference # of markers Identified Biomarker (s) Findings Estimates Biomarker Biomarker

tested application type
(identified)

Zhou et al.24 107 (22) Combination of 13 peptide markers
CD44(30–38), ZPI(438–444), FA5(1506–1517),
HEP2(469–483), HEMO(198–208), FETUA(58–67),
TSP1(217–228), DOPO(585–602), CRAC1(101–108),
PHLD(800–808), KNG1(479–496), C1R(683–689),
and VTDB(95–114). Combination of 11 peptide
markers ZPI(438–444), VTDB(364–370),
IC1(287–298), CD14(192–210), RET4(185–195),
HRG(140–153), PLF4(82–92), CRAC1(170–178),
SHBG(170–183), VTDB(128–149), C1R(683–689).
A set of 13 serum proteomic markers could
distinguish JSL and pain progressors from
non-progressors. A set of 11 serum proteomic
markers could distinguish JSL progressors
from non-progressors, and was validated in an
external cohort.
JSL and pain progressor vs. non-progressor: OA progression Protein
AUC=0.740 (0.669–0.772), from a model fit. JSL
progressor vs. non-progressor: AUC=0.698
(0.631–0.735), validation in an external cohort:
AUC=0.697.

8-OHdG: 8-hydroxy-2′-deoxyguanosine; aa: diacyl; ACAN: aggrecan core protein; ADL: activities of daily living; ae: acyl-alkyl; ALP: alkaline phosphatase; AR: alkylresorcinol; ARGS: ADAMTS-mediated aggrecan degradation
products; AUC: area under the curve; BDNF: brain-derived neurotrophic factor; C0: carnitine; C10C: cathepsin K-mediated type X collagen degradation fragment; C12: dodecanoylcarnitine; C14: tetradecanoylcarnitine; C14:2:
tetradecadienylcarnitine; C16:1: hexadecenoylcarnitine; C1R: complement C1r subcomponent; C2M: matrix metalloproteinase-mediated type II collagen degradation fragment; C3M: matrix metalloproteinase-mediated type III
collagen degradation fragment; CCC: cubic clustering criterion; CCL5: C-C chemokine receptor type 5; CCR7: C-C chemokine receptor type 7; CD14: monocyte differentiation antigen CD14; CD44: monocyte differentiation antigen
CD44; CILP-2: cartilage intermediate layer protein 2; CLU: clusterin; CML: carboxymethyllysine; COLL2_1: type II collagen degradation fragmen; COLL2_1NO2: inflammation-related (nitrated) type-II collagen degradation
fragment; COMP: cartilage oligomeric matrix protein; CRAC1: cartilage acidic protein 1; CRPM: matrix metalloproteinase-mediated c reactive protein degradation fragment; CRTAC1: cartilage acidic protein 1; CS: central
sensitization; CTXI: cross-linked, isomerised and cathepsin k-generated fragment of type I collagen C-terminal telopeptide; CTX-I: C-propeptide of type I collagen; CTXI_ALPHA: cathepsin K-generated fragment of type I collagen
C-terminal telopeptide; CTXII: matrix metalloproteinase- and cathepsin K-mediated type II collagen degradation fragment; CTX-II: C-propeptide of type II collagen; CVD: cardiovascular disease; CXCL: C-X-C motif chemokine
ligand; CXCR4: C-X-C chemokine receptor type 4; DDR2: discoidin domain receptor 2; DDw/oR: disc displacement without reduction; DJD-TMJ: degenerative joint disease of the temporomandibular joints; DM: diabetes mellitus;
DOPO: dopamine β-hydroxylase; FA 16:1: palmitoleic acid; FA 18:1: oleic acid; FA 18:2: linoleic acid; FA 20:4: arachidonic acid; FA 22:5: docosapentaenoic acid; FA5: coagulation factor V; FBN1: fibrillin-1; FETUA: alpha-2-HS
glycoprotein; GNLY: granulysin; HbA1c: glycosylated hemoglobin; HEMO: hemopexin; HEP2: heparin cofactor 2; HIV: human immunodeficiency virus; HMGB1: high mobility group box 1 protein; HR: hazard ratio; HRG:
histidine-rich glycoprotein; hsCRP: high-sensitive C-reactive protein; IC1: plasma protease C1 inhibitor; IHC: immunohistochemistry; IL: interleukin; JFLS-8: Jaw Functional Limitation Scale-8; JSL: joint space loss; JSN: joint space
narrowing; KL: Kellgren and Lawrence; KNG1: kininogen-1; KOA: knee osteoarthritis; KOOS: knee injury and osteoarthritis outcome score; LDD: lumbar disc degeneration; LDL-C: low density lipoprotein cholesterol; LOA: late
osteoarthritis; LPC: lysophosphatidylcholine; LRG1: leucine-rich alpha-2 glycoprotein; mCRP: monomeric C-reactive protein; MDA: malondialdehyde; MMP: matrix metallopeptidase; MRI: magnetic resonance imaging; NCAN:
neurocan core protein; NMID: bone gamma-carboxyglutamic acid-containing protein; NPY: neuropeptide-Y; NTX-1: N-telopeptide of type I collagen; OA: osteoarthritis; OARSI: Osteoarthritis Research Society International; OPG:
osteoprotegerin; OR: odds ratio; PBL: peripheral blood lymphocyte; PC: phosphatidylcholine; PGRN: progranulin; PHLD: phosphatidylinositol glycan–specific phospholipase; PIICP: procollagen type II C-terminal propeptide;
PLF4: platelet factor 4; PRO_C2: type IIB collagen propeptide; RANTES: regulated upon activation, normal T cell expressed and secreted; RE_C1M: matrix metalloproteinase-mediated type I collagen degradation; RET4: retinol-
binding protein 4; RR: relative risk; SERPINF1: pigment epithelium-derived factor; SF: synovial fluid; SHBG: sex hormone binding globulin; SM: sphingomyelin; TC: total cholesterol; TDO2: tryptophan 2,3-dioxygenase; TGs:
triglycerides; TKR: total knee replacement; TLR4: toll-like receptor-4; TMJOA: temporomandibular joint osteoarthritis; TNF-α: tumor necrosis factor-α; TSP1: thrombospondin-1; UKR: unicompartmental knee replacement; VAS:
visual analogue scale; VDBP: vitamin D-binding protein; VTDB: vitamin D binding protein; WOMAC: the Western Ontario and Mcmaster Universities Arthritis Index; ZPI: protein Z–dependent protease inhibitor.

Table 3
M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453

Results of individual studies.

1447
1448 M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453

Identified Biomarker (s) Reference Findings

CCL5 Feng et al.34 CCL5 ↑ in DDw/oR with early-stage TMJOA, can distinguish these patients from other DDw/oR patients.
Goode et al.75 CCL5 was one of the proteins in the panel to cluster OA patients.
Watanabe et al.35 Serum CCL5 ↑ in DJD-TMJ than in controls, positively associated with bone metabolism rate, especially in young
DJD-TMJ subjects, could distinguish DJD-TMJ from controls.
COMP Angelini et al.74 COMP was one of the proteins in the panel to cluster OA patients.
Hussain et al.15 COMP ↑ in KOA than in controls, and could distinguish KOA from controls.
Singh et al.14 COMP was negatively associated with medial femorotibial compartment cartilage thickness.
CRTAC1 Styrkarsdottir et al.22 CRTAC1 was positively associated with prevalent OA, predicted incident OA diagnosis and progression to joint
replacement. Individuals in the highest quintile of risk based on CRTAC1 level, age, sex, and BMI had a 9.8-fold risk of
knee or hip OA.
Szilagyi et al.13 CRTAC1 was positively associated with overall OA burden, hand OA and KOA severity and KOA progression.
Tardif et al.23 CRTAC1 was the most significant contributor to the panel discriminating OA from controls and ↑ in OA than in
controls.
Zhou et al.24 CRTAC1 was one of the proteins in the panel discriminating JSL and pain progressors from non-progressors, and in the
panel discriminating JSL progressors from non-progressors, and was validated in an external cohort.
CTX-I Angelini et al.74 CTX-I was one of the proteins in the panel to cluster OA patients.
Hussain et al.15 CTX-I ↑ in KOA than in controls, and could distinguish KOA from controls.
CTX-II Angelini et al.74 CTX-II was one of the proteins in the panel to cluster OA patients.
Goode et al.75 CTX-II was one of the proteins in the panel to cluster OA patients.
Liem et al.16 Baseline uCTX-II was associated with KL grade, medial JSN, lateral osteophytes, joint space width, and WOMAC pain
scores.
Lu et al.17 CTX-II ↑ in traumatic KOA than in controls, and ↑ in KL grade III+IV than in KL grade I+II group.
Glucose Chiba et al.54 In KOA patients with CS, glucose was negatively associated with changes in KOOS pain, ADLs, and sports scores from
baseline to 1-year follow-up.
Tudorachi et al.56 Glucose ↑ in OA than in controls and was associated with KOA risk.
Zheng et al.55 Poor glycemic control were associated with symptomatic KOA at 5-year follow-up. ↑ glucose were associated with ↑
risk of incident symptomatic KOA.
HbA1c Perruccio et al.42 Percentage of individuals with hsCRP level within published threshold for moderate/elevated CVD risk ↑ in OA and
multisite OA, which was predominant in men.
Zheng et al.55 ↑ HbA1c were associated with ↑ risk of incident symptomatic KOA.
hsCRP Angelini et al.74 hsCRP was one of the proteins in the panel to cluster OA patients.
Perruccio et al.42 Percentage of individuals with hsCRP level within published threshold for moderate/elevated CVD risk ↑ in OA and
multisite OA, which was predominant in women.
Ukibe et al.40 In postmenopausal women, hsCRP ↑ in OA than in non-OA.
Hyaluronic acid Angelini et al.74 Hyaluronic acid was one of the proteins in the panel to cluster OA patients.
Goode et al.75 Hyaluronic acid was one of the proteins in the panel to cluster OA patients.
LDL-C Nemet et al.57 Prevalence of high LDL-C ↑ in female KOA patients than in female controls.
Tudorachi et al.56 LDL ↑ in OA than in controls.
MMP3 Elamir et al.27 MMP-3 ↑ in KOA than in controls and could diagnose OA.
Singh et al.14 MMP-3 was negatively associated with patellar cartilage volume and total bone area after 4 years.
Singh et al.26 MMP-3 ↑ in OA than in controls, and positively correlated with KL grades, could distinguish between OA and controls
and different KL grades.
TC Nemet et al.57 Prevalence of high TC ↑ in female KOA patients than in female controls.
Tudorachi et al.56 TC ↑ in OA than in controls.
Uric acid Rifal et al.41 Hyperuricemia group had ↑ percentage of severe KOA compared to normal uric acid group, had a ↑ risk of
severe KOA.
Ukibe et al.40 In women, uric acid ↑ in OA than in non-OA.
VDBP Tardif et al.23 VDBP was one of the proteins in the panel discriminating OA from controls and ↑ in OA than in controls, which was
validated in an external cohort.
Zhou et al.24 VDBP was one of the proteins in the panel discriminating JSL and pain progressors from non-progressors, and in the
panel discriminating JSL progressors from non-progressors, and was validated in an external cohort.

ADL: activities of daily living; CCL5: C-C chemokine receptor type 5; COMP: cartilage oligomeric matrix protein; CRTAC1: cartilage acidic protein 1; CS: central sensitization;
CTX-I: C-propeptide of type I collagen; CTX-II: C-propeptide of type II collagen; CVD: cardiovascular disease; DDw/oR: disc displacement without reduction; DJD-TMJ:
degenerative joint disease of the temporomandibular joints; DM: diabetes mellitus; HbA1c: glycosylated hemoglobin; hsCRP: high-sensitive C-reactive protein; JSL: joint
space loss; JSN: joint space narrowing; KL: Kellgren and Lawrence; KOA: knee osteoarthritis; KOOS: knee injury and osteoarthritis outcome score; LDL-C: low density
lipoprotein cholesterol; MMP: matrix metallopeptidase; OA: osteoarthritis; TC: total cholesterol; TMJOA: temporomandibular joint osteoarthritis; VDBP: vitamin D-binding
protein; WOMAC: the Western Ontario and Mcmaster Universities Arthritis Index.

Table 4

Overlapping findings between studies.

Amirkhizi et al.38 found that KOA patients had lower levels of vi­
tamin D than controls. In KOA, compared with patients with suffi­
cient vitamin D, vitamin D insufficiency group had higher serum
levels of inflammatory biomarkers, which were inversely correlated
with serum vitamin D level, and higher WOMAC scores. Vitamin D
exerts metabolic functions through vitamin D receptors (VDRs) and
their activation could stimulate proteoglycan synthesis in mature
chondrocytes. In addition, binding of vitamin D to VDRs on immune
cells leads to immunomodulatory events. In case of vitamin D defi­
ciency, cartilage repair could be weakened and inflammatory re­
sponses increase leading to more severe OA symptoms.38
Inflammation-related biomarkers
Given the important role of inflammation in OA pathogenesis, in­
flammation-related biomarkers are also the focus of some studies. High-
sensitive C-reactive protein (hsCRP) is an established systematic
 M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453
inflammatory marker and uric acid has been suggested to be a factor
promoting the pathological process of OA through activation of the in­
flammasome.39 Ukibe et al.40 found that in human immunodeficiency
virus infected women, serum uric acid level was higher in OA patients in
premenopausal groups, and both CRP and uric acid levels were higher in
OA patients in postmenopausal groups compared with controls. Rifal
et al.41 found that the percentage of KL grade I-II patients was higher
than that of grade III-IV patients in the normal uric acid group, while it
was the opposite in hyperuricemia group, which had a greater risk of
experiencing severe KOA. Perruccio et al.42 reported that higher per­
centage of OA patients especially multisite OA patients had hsCRP and
glycosylated hemoglobin (HbA1c) levels within published threshold for
moderate/elevated cardiovascular disease (CVD) risk, pointing to a po­
tentially important role for inflammation in OA over and above tradi­
tional CVD risk factors. In two studies on pro-inflammatory
cytokines,43,44 it was found that serum interleukin (IL)-8 level was
higher in early KOA patients, and serum IL-17A level was higher in KOA
patients, specifically KL grade IV patients, than in controls, and positively
correlated with SF IL-17A level in OA patients. Serum and SF IL-17A levels
had positive correlations with pain and functional deficit scores with the
correlations being stronger for SF IL-17A, which also had strong positive
correlations with radiographic severity and duration of OA. Un­
gsudechachai et al.45 reported that the level of a multifunctional glyco­
protein clusterin was increased in KOA patients with synovitis than in
those without, greater in those with high-grade synovitis than in those
with low-grade or no synovitis, and positively associated with synovitis
severity, but the effect sizes were very small. Shao et al.46 found that SF
level of high mobility group box 1 protein (HMGB1) was higher in
TMJOA than in TMJ internal derangement (TMJID) group, and positively
correlated with pain and functional deficit scores and radiographic stage,
could distinguish TMJID from TMJOA. HMGB1 is a non-histone nuclear
protein that can serve as an alarmin which is released into the extra­
cellular space upon tissue injury or cellular activation to trigger in­
flammation and immune responses,47 which could contribute to OA
development and progression. Lu et al.17 reported that serum levels of
toll-like receptor-4 (TLR4) and C-X-C motif chemokine ligand (CXCL)12
were higher in traumatic KOA patients than in controls, and higher in KL
grade III+IV than in KL grade I+II group. The activation of TLR4 signaling
pathway leads to host responses in the form of de novo expression of
genes such as inflammatory cytokines, and is followed by the production
of chemokines and cytokines.48 CXCL12 has the ability of inducing
chondrocyte hypertrophy, and by binding to its receptors C-X-C che­
mokine receptor type 4 (CXCR4) on chondrocytes, it can regulate many
homeostatic and pathological processes during the progression of OA via
the activation of downstream signaling pathways.49 Interestingly, an­
other study conducted by Trajerova et al.50 showed that elevated ex­
pression of CXCR4 was linked to persistent KOA symptoms. Cheng et al.51
and Sodhi52 et al. found that SF C3-α and C3-β levels were correlated
with the KOA severity and higher in the OARSI grade ≥6 group. In
male patients, increased SF C5 level was associated with lower
vascularization scores and higher SF level of terminal complement
complex sC5b-9. Vascularization scores indicate wound healing
and sC5b-9 level indicates complement activation. Their finding
raised the hypothesis that the positive association between com­
plement signaling and OA outcomes might be due to the inhibition
of synovial vascularization in OA. However, the effect size was quite
small and the findings need further validation. In a lipidomics
study, Loef et al.53 discovered that lipidomics accounted for a small
portion of the variance in OA severity, pain, and function, which
were associated with the lipidomic fraction of bound and free
arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid,
and docosapentaenoic acid (FA 22:5), with FA 22:5 being a newly
discovered lipid species associated with OA. This study only pre­
sented R2 not p values which made it difficult to evaluate the sig­
nificance of the identified metabolites.
1449
Metabolism-related biomarkers
A number of metabolism-related biomarkers were reported in
the past year including the most commonly recognized glucose
and HbA1c, blood lipids total cholesterol (TC), low density lipo­
protein cholesterol (LDL-C), and triglycerides (TGs), obesity and
energy homeostasis hormone adropin, and aging biomarker car­
boxymethyllysine (CML). Chiba et al.54 found that in OA patients
with central sensitization, glucose level at baseline was negatively
associated with changes in pain, activities, and sports scores from
baseline to one-year follow-up. Zheng et al.55 found that study
participants with diabetes mellitus (DM) and HbA1c≥7% were
more likely to develop symptomatic KOA at 5-year follow-up
compared to those without DM. Higher levels of HbA1c and
fasting blood glucose were associated with higher risk of incident
symptomatic KOA. Tudorachi et al.56 reported that levels of TC,
LDL, TGs, and glucose were higher in OA or severe OA patients, and
glucose level was associated with KOA risk, but the predictive
power was low compared to other factors such as sex, body mass
index, and environment of origin. Nemet et al.57 reported that in
female, fasting glucose and TG levels and percentages of patients
with high TC and LDL-C levels were all higher in KOA patients than
in controls. These studies demonstrated that metabolic syndrome
components could contribute to OA development and progression.
Selim et al.58 studied adropin, a protein that participates in energy
homeostasis and the control of fatty acid and glucose metabolism,
and found that serum adropin level in KOA patients was lower
than in controls, and lower in females than in males in OA pa­
tients. Serum adropin level was negatively correlated with KL
grading and could distinguish between KOA patients and controls.
Cambon-Binder et al.59 discovered that serum CML concentration
was lower in erosive than in non-erosive hand OA, and cartilage
CML concentration was higher in OA than in non-OA metacarpo­
phalangeal (MCP) joints. However, only five OA MCP joints were
included in the analysis. Their findings seem to suggest that CML
plays different roles in bone erosion and cartilage degeneration
but need further validation.
Oxidative stress-related biomarkers
Jitjumnong et al.60 reported that plasma levels of two previously
discovered oxidative stress-related biomarkers, 8-hydroxy-2′-deox­
yguanosine (8-OHdG) and malondialdehyde (MDA) were higher in
lumbar disc degeneration (LDD) patients than in controls, and po­
sitively correlated with LDD severity. 8-OHdG is a biomarker of
oxidative DNA damage and MDA is an end-product of lipid perox­
idation. These evidences showed that higher level of oxidative stress
was present in LDD patients, and plasma 8-OHdG and MDA may
have potential as noninvasive biomarkers for the assessment of LDD
severity.
Novel biomarkers/biomarker panels
A number of novel biomarkers/biomarker panels were re­
ported in the past year. Shekhar et al.61 reported that serum MMP-
17 level was higher in KOA and increased with disease severity,
and could distinguish KOA patients from controls. Higher serum
MMP-17 level was associated with higher risk for having advanced
stage KOA. Sarkar et al.62 showed that in plasma, leucine-rich
alpha-2 glycoprotein (LRG1) level was increased in OA patients
compared to controls. In SF, LRG1 level was higher in OA patients
who underwent total knee replacement (TKR) than in those who
underwent unicompartmental knee replacement. LRG1 was
identified as one of the important proteins that might play a
central role in fibrosis in OA. In the previously mentioned study on
CRTAC123, the authors also found that serum levels of vitamin D
binding protein (VDBP), fibrillin-1 (FBN1), and pigment epithe­
lium-derived factor (SERPINF1) were all upregulated in OA
1450 M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453
patients than in controls, and validated their findings in another
independent cohort except for SERPINF1. Three peptides of VDBP
were reported in another study to be associated with OA radio­
graphic and/or pain progression over 48 months.24 VDBP was also
found to be the second contributor in the component dis­
criminating OA from controls in this study, and has been pre­
viously reported to be upregulated in skeletal muscles from end-
stage KOA patients.63 FBN1 is an extracellular matrix protein that
has been reported to regulate the bioavailability of the latent
transforming growth factor beta-1 complex, a key factor involved
in OA cartilage and bone.64 Liang et al.65 found that plasma C-
reactive protein monomer (mCRP) level was higher in OA patients
than in controls and higher in KL grade IV than in KL grade III
patients, and had a better predictive performance for diagnosing
OA than CRP. mCRP is the monomeric form of CRP and the main
active conformation of local tissues. Compared to CRP which is a
non-specific inflammatory marker, mCRP is considered to play a
role by depolymerizing pentamer CRP into monomer form in the
local tissue of the lesion and may be a more sensitive indicator in a
specific disease. Another newly discovered inflammation-related
protein biomarker for OA was tryptophan 2,3-dioxygenase (TDO2).
Rong et al.66 reported that synovium level of TDO2 was higher in
OA and could discriminate OA patients from controls. In OA pa­
tients, TDO2 level was positively correlated with pro-in­
flammatory cytokine levels in synovium and SF, and synovium
TDO2 level was positively correlated with KL scores. TDO2 is the
primary enzyme that catabolizes tryptophan to kynurenine and
has been suggested to be involved in inflammation-related dis­
eases. However, the sample size of this study was small and the
controls were patients that had meniscal injury, which could have
affected the TDO2 level of the control group. Drvar et al.67 found
that in female, the intensity of granulysin (GNLY) labeling in
peripheral blood lymphocytes was higher in KOA than in controls.
More investigations were done in this study using cells to de­
monstrate that GNLY-mediated apoptosis of K-562 targets was
higher in KOA patients alongside lymphocyte pro-inflammatory
polarization. However, this study needs to be broadened with a
larger cohort and different OA phenotypes in both sexes to reach a
definitive conclusion. In addition to these protein biomarkers, a
few new metabolite biomarkers for OA were reported in relatively
large cohorts. Xie et al.68 identified C16:1/C14 and C16:1/C12 to be
positively associated with patellar cartilage volume loss, sug­
gesting the involvement of altered long chain fatty acid β-oxida­
tion in this process. Zertuche et al.69 found that baseline level of
alkylresorcinol, a marker of whole grain intake, was associated
with a reduced risk of radiographic KOA at 30-month, but this
association did not hold for symptomatic KOA at 30-month or 60-
month cumulative outcomes. This study provided an uncertain
but suggestive result that high fiber intake might protect against
KOA. Sasaki et al.70 identified 42 plasma metabolites to be corre­
lated with OA severity in female, indicating that urea cycle and
tricarboxylic acid (TCA) cycle were the key metabolic pathways in
OA, and the level of cysteine, an amino acid associated with an­
tioxidant activity and glutamate homeostasis, was moderately
associated with radiographic OA. Zhou et al.24 identified a set of 13
serum proteomic markers that could distinguish KOA joint space
loss and pain progressors from non-progressors, better than tra­
ditional prediction based on baseline structural OA and pain se­
verity or urinary CTX-II. A set of 11 serum proteomic markers
could distinguish JSL progressors from non-progressors, and was
confirmed in a validation cohort. These two biomarker panels had
higher predictive power for clinically relevant KOA progression
than single protein markers, and provided a basis for future de­
velopment of means of identifying individuals most in need of
surveillance and disease modifying therapies.
Biomarkers for OA clustering
Trajerova et al.50 identified four immune-phenotypes in KOA, and
found that elevated CXCR4 and CCR7 expression on macrophages
and low CXCL10 in SF were linked to the persistence of KOA symp­
toms. All three of these proteins have been previously linked to OA
with CXCR4 signaling being involved in the expression of matrix-
degrading enzymes,71 CCR7 deficiency leading to delayed develop­
ment of joint damage and functional deficits,72 and CXCL10 playing
an important role in tissue repair.73 Angelini et al.74 identified three
KOA clusters based on the concentrations of 16 baseline serum and
urine biochemical markers reflecting joint tissue turnover. Cluster 1
(C1) represented a low tissue turnover phenotype and had the
highest proportion of non-progressors; cluster 2 (C2) represented a
structural damage phenotype and was mostly linked to longitudinal
structural progression; cluster 3 (C3) represented a systemic in­
flammation phenotype and was linked to sustained or progressive
pain. The authors also validated the clustering in an independent
cohort. However, the cluster separation in the discovery cohort was
vague, and all markers showed differences in median cluster values
between the discovery and validation cohorts. Goode et al.75 iden­
tified three OA clusters based on profiles of 10 serum and urine
protein/metabolite biomarkers associated with lumbar spine struc­
tural changes, inflammation, or pain. C1 was a structural change
subgroup characterized by a higher percentage of lumbar spine
structural changes; C2 was a reference subgroup with lower levels of
biomarkers, pain, and structural degenerative changes; C3 was a
pain and inflammation subgroup with higher levels of structure and
inflammation-related biomarkers and pain. These findings may have
utility for differentiating particular subgroups of patients who may
have a nociception generating structure resulting in pain, which may
help increase targeting specificity when considering interventions.
In addition to protein biomarkers, OA clustering was also explored
using metabolites. Rockel et al.76 identified two end-stage KOA
clusters based on plasma concentrations of 151 metabolites, and 24
metabolites could predict cluster classification, highlighting en­
riched tRNA acylation and B-vitamin metabolism pathways. This
study was unable to examine the differences in OA clinical pheno­
types or trajectories of the two clusters as this was a cross-sectional
study and all participants were end-stage OA patients under­
going TKR.
Biomarkers for OA treatment outcomes
The most effective treatment for end-stage KOA is TKR, yet a
great portion of patients still report pain post-TKR. Using meta­
bolomics profiling and meta-analysis, Costello et al. 4 found that
plasma phosphatidylcholine (PC) diacyl (aa) C28:1 concentration
and PC aa C28:1/PC aa C32:0 were negatively associated with
sustained pain post TKR, while PC aa C32:0/PC aa C28:1 and
C14:2/sphingomyelin C20:2 were positively associated, sug­
gesting potential roles of inflammation, oxidative stress, pain
sensitization and altered lipid metabolism in sustained pain
in KOA.
Conclusion
The majority of the studies published in the past year investigated
biomarkers for OA or OA severity/progression. However, the number of
studies exploring biomarkers for OA endotypes is rising, and three OA
subtypes, low progression, structure change, and inflammation with
pain, have been consistently identified using protein and metabolite
biomarker panels in two separate studies on knee and spine, respec­
tively.74,75 A number of previously discovered biomarkers related to
cartilage/bone structure, inflammation, metabolism, and oxidative stress
 M. Liu et al. / Osteoarthritis and Cartilage 31 (2023) 1437–1453
were reported with MMPs, CTX-II, COMP, and CRTAC1 being identified in
multiple studies, although the predictive powers of these biomarkers
need to be carefully considered and further investigated as all these
proteins had small effect sizes in most of the studies. Among the newly
discovered biomarkers, increasing number of metabolites were reported
and they pointed out several pathways including urea cycle, TCA cycle,
tRNA acylation, B-vitamin metabolism, pain sensitization, and altered
lipid metabolism to be associated with OA severity/progression, en­
dotypes, and treatment outcomes,4,68,70,76 which may assist in eluci­
dating pathogenesis of OA and developing new interventions. Several
studies explored biomarker panels for OA progression24 and clus­
tering74–76 and demonstrated that biomarker panels might have better
predictive powers compared to individual markers, at least for OA pro­
gression.24 Combination of biochemical markers with other types of
makers (e.g., imaging markers, clinical factors, etc.) might also be a better
strategy to predict OA severity and progression.16,53 The major limitation
of the studies published in the past year is that nearly half of these
studies had small (n < 50) or very small (n < 20) sample sizes in at least
one study group, and most studies did not validate their findings or
models in other independent cohorts, which could limit broader clinical
applicability of discovered markers. Moreover, in the real-life clinical
practice, the most needed biomarkers are the ones that can help identify
OA patients among individuals with joint symptoms, whereas most of
these studies compared OA patients with healthy controls or individuals
without joint pain. OA biomarker studies should be taken one-step
further and the design of the studies should be carefully considered to
connect the lab findings with clinical applications. Despite these lim­
itations, these discoveries may help better understand the pathogenesis
of OA, provide potential therapeutic targets and insights into possible
mechanisms underlying poor treatment outcomes, and aid in developing
personalized or stratified interventions based on OA subtypes.
CRediT authorship contribution statement
Ming Liu: Literature search and data acquisition, Data analysis
and interpretation, Drafting original manuscript, Critical manuscript
revision and approval of final manuscript. Nafiza Haque: Literature
search and data acquisition, Data analysis and interpretation, Critical
manuscript revision and approval of final manuscript. Jingyi Huang:
Literature search and data acquisition, Data analysis and inter­
pretation, Critical manuscript revision and approval of final manu­
script. Guangju Zhai: Conception and design, Literature search and
data acquisition, Data analysis and interpretation, Critical manu­
script revision and approval of final manuscript.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgements
This study was supported by the Canadian Institutes of Health
Research (FRN#175015; 153298; 143058; 132178). The funder had no
role in the design of the study; in the collection, analyses, or inter­
pretation of data; in the writing of the manuscript, or in the decision
to publication.
Appendix A. Supporting information
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.joca.2023.08.005.
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