Received: 28 August 2019 | Accepted: 11 February 2020

DOI: 10.1002/jor.24630

REVIEW

Molecular biology of meniscus pathology: Lessons learned

from translational studies and mouse models

Muhammad Farooq Rai PhD1,2 | Robert H. Brophy MD1 | Vicki Rosen PhD3

1
Department of Orthopedic Surgery,
Washington University School of Medicine, Abstract
St. Louis, Missouri
2 Injury to any individual structure in the knee interrupts the overall function of the
Department of Cell Biology & Physiology,
Washington University School of Medicine, joint and initiates a cascade of biological and biomechanical changes whose endpoint
St. Louis, Missouri
is often osteoarthritis (OA). The knee meniscus is an integral component of knee
3
Department of Developmental Biology,
Harvard School of Dental Medicine, biomechanics and may also contribute to the biological homeostasis of the joint.
Boston, Massachusetts Meniscus injury altering knee function is associated with a high risk of OA pro-
Correspondence gression, and may also be involved in the initiation of OA. As the relationship
Muhammad Farooq Rai, Department of between meniscus injury and OA is very complex; despite the availability of
Orthopaedic Surgery, Washington University
School of Medicine, 425 S. Euclid Ave. transcript level data on human meniscus injury and meniscus mediated OA,
MS 8233, Saint Louis, MO 63110. mechanistic studies are lacking, and available human data are difficult to validate
Email: rai.m@wustl.edu
in the absence of patient‐matched noninjured control tissues. As similarities exist
Vicki Rosen, Department of Developmental between human and mouse knee joint structure and function, investigators have
Biology, Harvard School of Dental Medicine,
188 Longwood Avenue, Boston, MA 02115. begun to use cutting‐edge genetic and genomic tools to examine the usefulness of
Email: vicki_rosen@hsdm.harvard.edu the mouse as a model to study the intricate relationship between meniscus injury

Funding information
and OA. In this review, we use evidence from human meniscus research to identify
National Institute of Arthritis and critical barriers hampering our understanding of meniscus injury induced OA and
Musculoskeletal and Skin Diseases,
Grant/Award Numbers: AR064837, AR074992
discuss strategies to overcome these barriers, including those that can be examined
in a mouse model of injury‐mediated OA.

KEYWORDS

genetics and genomics, meniscus, osteoarthritis, repair

1 | INTRODUCTION factors.3 Moreover, a number of genetic components have been

The knees are the largest synovial joints in the human body and
are among the joints most commonly affected by the highly pre-
valent degenerative disease known as osteoarthritis (OA). Despite
extensive research, the etiology and pathogenesis of primary
idiopathic OA are not fully understood. Although the increasing
prevalence of OA has been attributed, at least in part, to an in-
1,2
crease in life expectancy and the obesity epidemic,
study has, however, reported that the high prevalence of OA
cannot be explained by increases in longevity and obesity alone,
necessitating the identification of additional independent risk
linked to OA,4 and it is likely that identification of additional
genetic susceptibility variants will augment our understanding of
individual susceptibility to primary knee OA. In contrast to primary
OA, secondary OA occurs after an injury, and an injury to any
individual knee structure(s) disrupts the normal function of the
knee and initiates a cascade of biological and biomechanical
changes, which often terminate in posttraumatic OA.5
a recent The meniscus, a fibrocartilaginous structure found in the knee
(and also in the jaws), is an integral part of the complex biomechanics
of the knee joint and may also contribute to the biological
homeostasis of other knee joint structures, including the articular

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© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

J Orthop Res. 2020;1–10. wileyonlinelibrary.com/journal/jor | 1

2 |
cartilages of the femur and the tibia. Meniscal injury frequently alters
knee functions and often leads to progressive degenerative disease
of the joint. Traumatic meniscal tears are common in young,
active individuals and as a result, approximately 690 000 partial
meniscectomies and almost one million additional knee arthroscopies
6,7
are performed every year in the United States. Meniscal resection
for traumatic or degenerative meniscal tears is reported to be
associated with a two to sevenfold risk of development of
symptomatic knee OA.8,9 While altered tibiofemoral contact force
and joint destabilization resulting from injured meniscus appear to be
the primary drivers for OA initiation, a clear mechanistic
understanding of how meniscus injury/degeneration initiates a cas-
cade of molecular events leading to OA remains elusive.
In this review, we use evidence from human meniscus research
to discuss critical barriers hampering our understanding of the
pathogenic mechanisms of meniscus injury induced OA. These
barriers include the heterogeneous nature of meniscus, both in
terms of structure and function; the influence of both intrinsic and
extrinsic confounders (risk factors); lack of understanding of the
capacity of the meniscus to regenerate due to limited success in
enhancing meniscus healing with available treatments; and, lack
of availability of patient‐matched noninjured controls. These
significant obstacles currently preclude the development of a
mechanistic understanding of meniscus injury induced OA that
would not only provide important insights into the pathogenesis of
OA but also help identify targets for therapeutic intervention.
Finally, we discuss strategies to overcome the aforementioned
barriers, including the utility of a mouse model predictive of me-
niscus injury mediated OA.
2 | TH E MEN I S CUS IS A C O M PL EX
S T R U C T U R E T H A T PE R F O R M S D I V E R S E
FUNCTIO NS R EQUIRED F OR OPTIMAL
KNEE JOINT FUNCTION
Human menisci are C‐shaped structures located between the
femoral condyle and the tibial plateau within the knee. Composed
primarily of fibrocartilage endowed with high water content, the
menisci are strong, flexible, and resilient.10 Menisci perform
diverse functions critical to normal knee physiology. Physically, they
distribute loads across the knee and provide a low friction surface
for joint movement.11 Biologically, menisci contribute to the
composition of synovial fluid12,13 and communicate, via production
of both biomechanical and biological signals (such as inflammatory
pathways, anabolic and catabolic markers, and immune system
pathways) with the adjacent articular surfaces of the tibia and
femur, and perhaps the synovium and other tissues in the knee joint
as well.14 Often underappreciated is the structural and
cellular complexity of the meniscus that allows for these functions.
When injured, impaired meniscus function has a huge impact on
joint physiology, increasing the risk for development of OA, and
15,16
contributing to poor joint health and disability.
RAI ET AL.
2.1 | Structural heterogeneity of meniscus
Each meniscus can be divided into an anterior horn, body, and
posterior horn, and can also be divided into an outer region, middle
region, and inner region.17 Anatomically, the outer edges and ends of
each meniscus are attached to the tibia by ligaments. The inner edges
lack attachments, allowing for frequent adaptation in meniscus shape
with joint movements. The vascularity of the meniscus is described as
consisting of three zones. The outer red‐red zone is essentially at the
meniscus‐capsule junction and has excellent vascularity and potential
for healing of meniscal repairs. Moving centrally, the middle
red‐white zone has intermediate vascularity and healing potential.
The inner white‐white zone has essentially no vasculature and
minimal healing potential. It is important to note that the healing
capacity of the meniscus varies by region; meniscus outer regions
that contain ample vasculature and neuronal signals are more likely
to initiate a regenerative response than the meniscus inner region,
a more cartilage‐like structure.18 It is thought that the lack of
vasculature in the inner and middle regions of the meniscus is
responsible for the low reparative and regenerative capability that
occurs after injury in this region.18
2.2 | Cellular heterogeneity of the meniscus
Unlike articular cartilage which consists of only one cell type, the
meniscus is comprised of several distinct cell populations with
unknown lineage relationships to one another.19 The main cell type in
the inner and middle regions of the meniscus is the fibrochondrocyte,
a round or oval‐shaped cell surrounded by abundant extracellular
matrix.20 The major fibrillar collagen produced by meniscus
fibrochondrocytes is type II collagen.21 Meniscus fibrochondrocytes
stain negatively for a cluster of differentiation (CD) 34, a surrogate
marker for hematopoietic stem and progenitor cells. In addition to
fibrochondrocytes, the inner avascular region of the meniscus also
harbors a unique progenitor cell population that exhibits multilineage
differentiation potential and migratory activity.22 In contrast,
the outer region of the meniscus consists predominantly of spindle‐
shaped fibroblast‐like cells within a dense connective tissue matrix20
composed mainly of type I collagen.23 These cells exhibit positive
staining for CD34 but are negative for CD31, a marker for platelet‐
endothelial cells. It is suggested that this cell type contributes to
the healing capability of the outer meniscus since the presence of
the vasculature is an important factor in this as well.24
3 | C U R R EN T TR EA T M EN T O F M EN I SC U S
IN J U RI E S I S O N L Y P A R T I A L L Y S U C C E SS F U L
There is now an increased realization that surgeries aimed at saving the
meniscus are preferable to meniscus removal.25 Currently, three types
of surgical managements are in practice: meniscus repair, arthroscopic
partial meniscectomy, and meniscus replacement or transplant.26
RAI ET AL.
The structural diversity of the meniscus allows for tailored approaches
for the treatment of meniscus injuries based on their location. Repair is
most often performed in tears occurring in posterior medial region of
the meniscus27 as the tears within this zone are the most amenable to
28
interventions. Recently, because of increased awareness of the
significance of meniscus preservation and associated degenerative
25
(osteoarthritis) changes due to meniscectomy, there has been an
attempt to expand repair to include tears in more locations and with
different configurations. Partial meniscectomy is a procedure in which
damaged fragments of the meniscus are debrided while preserving as
much meniscus tissue as possible. While both meniscus repair and
partial meniscectomy may be acceptable treatment options for certain
types of meniscus tears, meniscal repairs have a higher reoperation
rate than partial meniscectomies, although the repair is associated with
better long‐term outcomes.29,30 Meniscus repair techniques are
considered to be a significant challenge for lesions found in the inner
avascular region, primarily due to the lack of blood supply and perhaps
in part because this inner avascular zone appears devoid of stem
cell populations.24 As such, evolving techniques for meniscus
reconstruction employing implantation of meniscus substitutes with or
without exogenous stem cells and/or growth factors are being explored
in this setting.31 When a substantial portion of the meniscus is
damaged or deficient, meniscus transplantation of fresh or frozen
32
meniscal allografts is the last remaining treatment option. The
biological and synthetic substitutes must possess the anatomical,
biological and mechanical characteristics of the meniscus, making their
utility limited by availability.
4 | M U L T I T U D E O F FA C T O R S I N F L U E N C E
MENISCUS PATHOLOGY
A multitude of (risk) factors can influence meniscus biology, injury,
and repair. Biomechanics obviously play an important role in terms
of how meniscal resection impacts the joint overall but the focus
of this review is on other factors that impact the biology of the
underlying meniscus. Each factor may work independently or in
concert with other factors, further highlighting the complexity of
meniscus biology and pathology. Some of the most important factors
are discussed here and summarized in Table 1.
4.1 | Age
Like any musculoskeletal tissue, the biology of the meniscus is
impacted by aging. It has been reported that increasing age is
associated with an increased risk for meniscus injury33 and the
prevalence of degenerative meniscal lesions frequently increases with
age.35 Further, it has been reported that aging heightens the risk for
complications after meniscus surgery.34 However, there is some
discrepancy in the literature with regard to the impact of age on
meniscus repair. While some authors have reported that young
patients are the best candidates for a meniscal repair because of their
| 3
greater healing potential,46,47 others have reported that patients,
under the age of 30 years, experience significantly higher rates of
subsequent meniscectomies than older patients and that meniscal
repairs healed equally well in young and old patients.48,49
Microarray analysis of injured menisci has revealed that gene
signatures associated with the immune response, inflammation, cell
cycle, and cellular proliferation are increased with age, whereas genes
associated with cartilage and skeletal development and extracellular
matrix synthesis are repressed with age, suggesting a distinct
phenotype of meniscus degeneration with aging.45 From a mechanistic
perspective, autophagy, a natural cellular homeostasis mechanism that
facilitates normal cell function and survival by removing unnecessary
or dysfunctional components and allowing the orderly degradation and
recycling of cellular components,50 is also significantly changed in the
meniscus during aging. Aging and injury can lower basal levels of
autophagy and result in meniscus degeneration and development of
OA.51 Conversely, induction of autophagy has been shown to
significantly reduce the severity of OA.52
4.2 | Sex
There is a consensus, and available data strongly supports the
observation that females are more affected and burdened by knee
OA than males.53 Rates of anterior cruciate ligament (ACL) tears
are also higher in women than men when engaged in similar
activities.54 Men, however, have a greater prevalence of meniscus
injury than women.33 There are relatively small differences observed
in gene expression of meniscus tissue when segregated by sex, with
a need for more investigation in this area.
4.3 | Genetics
Interestingly, it has been noted that meniscus damage also occurs in
the absence of knee trauma,35 suggesting that factors other than
acute injury could contribute to this damage. One study provided
evidence for genetic predisposition for meniscus damage.36 In this
study, authors used the Framingham cohort to determine whether
radiographic hand OA is associated with meniscus damage by
examining the correlation of finger OA on hand radiographs, and
the number of fingers affected by OA, with the presence of meniscus
damage. The prevalence of meniscus damage was 24.9% to 47.2%
and was positively associated with the number of fingers affected
by OA. This observation supports the concept of a common
systemic/genetic predisposition and/or a common environmental
risk factor for radiographic hand OA and meniscus damage.
4.4 | Obesity
Obesity has a strong impact on meniscus health; it is associated
with a high risk of the first hospitalization due to meniscus
4 | RAI ET AL.

T A B L E 1 Factors that contribute to meniscus injury and pathology

Factor Functional attribute Reference

Age Increased risk for meniscus tear Jones et al33

Heightened risk for complications after meniscus surgery Abram et al34
Increased risk for meniscus degeneration Englund et al35

Sex Female sex is associated with lower risk for meniscus tear Jones et al33

Genetics Genetics increases predisposition to meniscus damage Englund et al36

Obesity Increased risk of first hospitalization due to meniscus lesions Kontio et al37
Decreased knee flexion after arthroscopic partial meniscectomy Kluczynski et al38
Increased incidence of medial meniscus body extrusion Zhang et al39

Activity level High activity levels, e.g., service in Armed Forces is associated with increased incidence Jones et al33
of meniscus injury
Participation in ball playing sports, gymnastics and jogging predict the highest risk of Kontio et al37
meniscus lesions
A gradual increase in activity (e.g., frequency, duration, and intensity) may be warranted Cattano et al40
prior to returning to activities that involve running

Time from injury Duration of complaint is associated with heightened risk of meniscectomy Jiang et al41
Shorter duration of symptoms prior to partial meniscectomy is associated with a greater Haviv et al42
improvement in clinical symptoms after surgery

Prior knee injury and Prior ACL tears is associated with a decreased risk of meniscectomy Jiang et al41
surgery Young people with ACL injuries have a very high associated incidence of meniscal disease Reid et al43
at the time of corrective surgery

Tear pattern Root tear is associated with increased pain MacFarlane et al44
Young patients with ACL tears have a very high prevalence of meniscal pathology Reid et al43
Strong association between ipsilateral meniscus tear and medial meniscus body extrusion Zhang et al39
No predictable relationship between meniscal damage and meniscal symptoms MacFarlane et al44

Status of the articular A weak evidence exists to establish a link between early degenerative changes in the Rai et al45
cartilage cartilage and gene expression in meniscus

Abbreviation: ACL, anterior cruciate ligament.

lesions,37 and decreased knee flexion after arthroscopic partial
38
meniscectomy. Medial meniscus body extrusion is more
common in patients with elevated body mass index (BMI).39
Transcriptome profiling of fragments of injured meniscus showed
that higher BMI is negatively associated with extracellular
matrix gene transcripts in human injured meniscus. 55 Interest-
ingly, greater gene expression differences exist between obese
and overweight patients than obese and lean patients or between
lean and overweight patients. Gene ontology analysis revealed
that biological processes related to oxygen transport, calcium‐
binding, extracellular matrix, metal ion binding, and metabolic
process were enriched in the obese and lean or overweight
comparison. In contrast, no significant biological processes other
than axon guidance were enriched for the lean and overweight
comparison. This finding suggests that there is a weight‐threshold
at which injured meniscus has a magnified response to increased
body weight. Additionally, obesity‐related changes in gene
expression present a plausible explanation for how the biology
of the meniscus may contribute to the elevated risk of OA in
obese patients. Adipose tissues are a major source of cytokines,
chemokines, and metabolically active mediators called adipokines
(or adipocytokines) including leptin, resistin, adiponectin, and
visfatin.1 These adipokines play important roles in metabolic
homeostasis through autocrine, paracrine, and endocrine signal-
ing56 and provide a critical nonbiomechanical link between
obesity and OA.57 A detailed description of how adipokines
impact metabolic homeostasis and OA is reviewed in Rai and
Sandell. 1 While adipokines exert catabolic and anti‐anabolic
effects both on meniscus and articular cartilage, meniscus has
been shown to be more susceptible to adipokine‐stimulated
catabolism than articular cartilage.58 Additionally, specific
adipokines play different roles in meniscus homeostasis and
injury. For instance, visfatin, but not leptin, exerts catabolic
effects on the meniscus,59 while adiponectin and resistin have
been shown to be higher in meniscus tear patients with early
degenerative changes on radiographs. 60
4.5 | Level of activity
The activity level of the individual is a very important factor in
determining the rate of meniscus damage. It has been reported
that members of the armed services (Army and Marine Corps)
have an increased incidence of meniscus injury.33 Participation in ball
RAI ET AL.
related sports, gymnastics and jogging predict a higher risk of
meniscus lesions.37 Moreover, occupational hazard such as kneeling
has also been reported to influence meniscus degeneration as
degenerative tears were reported to be more prevalent in individuals
with increased kneeling such as floor layers compared to those with
less kneeling such as graphic designers.61
4.6 | Time from injury
While there is a fair amount of literature on the significance of
the time of intervention versus time from injury in ACL tears,62–65
little is known about the impact of time from injury on intervention
after meniscal tears. There is one report suggesting that the duration
41
of symptoms is associated with a heightened risk of meniscectomy
but meniscal symptoms may not be obvious after meniscus injury.
Clinical data suggest that a shorter duration of symptoms prior to
partial meniscectomy is associated with a greater improvement in
clinical symptoms after surgery.42
4.7 | Concomitant knee injury and surgery
A prior knee injury is associated with a decreased risk of
meniscectomy.41 However, it has been reported that young people
with ACL injuries have a very high associated incidence of meniscal
disease at the time of surgery.43 A comparison of gene expression
signatures in isolated meniscus tears versus meniscus tears with
concomitant ACL tears found increased inflammation and depressed
matrix synthesis in combined injuries, suggesting that the meniscus
appears to undergo more substantial molecular changes as a result
of combined injury.66
4.8 | Tear pattern
Meniscus tear is a known predisposing factor for the development of
posttraumatic OA and meniscus tears account for 12% of all knee
OA.67 Approximately 50% of people with meniscal tears have
radiographic evidence for OA 6 to 20 years after injury68,69 suggesting
that meniscus injury represents a sentinel event for early‐stage OA.
While meniscus tears can present with a wide range of patterns, they
are generally classified as traumatic and degenerative.
A recent study found that the gene expression signatures in
injured meniscus vary based on the nature of tear (degenerative vs
traumatic), a finding that may have important implications for both
the varying potential for healing following meniscus repair and for
the differential risk for developing OA.43 Traumatic (vertical) tears
expressed higher levels of chemokines and matrix metalloproteases
(MMPs) and lower levels of collagen than degenerative (complex,
horizontal, or flap) tears. However, to date, no predictable
relationship between meniscal tear patterns and meniscal symptoms
has been established.44
| 5
5 | RE LATIONSHIP B ETWEE N M E NISCUS
IN JU RY AN D O A I S NOT FU LLY
ELUCIDATED
Current patient data suggest a strong link between meniscus injury
and knee OA,47,70–76 but also suggests that this linkage is complex
(Figure 1). The role of the meniscus in the initiation and progression
of OA is thought to be minimal unless injured.68,77 Once injured,
emerging evidence suggests that meniscus injury disrupts a number
of key biological processes and signaling pathways leading to joint
degeneration (Table 2). Meniscus cells secrete inflammatory
cytokines and degradative enzymes in response to injury or altered
loading81,82; these signals then affect meniscal cell biology, limiting
the native repair potential of meniscus lesions in vitro and likely in
vivo.83 Deleterious effects of injury and/or aging on the meniscus can
also affect the homeostasis of other joint tissues, including the
synovium and articular cartilage,12,78,79,82,84–86 likely via secreted
MMP activity provided by injured meniscus cells.86–90 Additionally,
studies comparing torn meniscus from knees undergoing partial
meniscectomy to OA knees revealed that menisci undergoing partial
meniscectomy exhibited a repair phenotype compared to the
inflammatory profile seen in the OA meniscus,70,71 a finding that
suggests that the meniscus gene expression profile changes both
with injury and degeneration and that these profiles are distinct from
one another.91,92 Taken together, current information clearly
suggests a biological role for the meniscus in knee OA. One plausible
scenario is that meniscal damage induces mechanical instability
and increases loading stress in the knee; this, in turn, stimulates the
production of catabolic proteins such as cytokines, chemokines, and
matrix‐degrading enzymes by joint tissues and over time results in
OA.82 It is also possible that the initial response of the meniscus to
injury could be a repair response, which interacts with the other
tissues in the knee in a manner that switches this repair potential
into catabolic signals that lead to tissue breakdown.
Unfortunately, developing a mechanistic understanding of
meniscus‐mediated OA is very difficult to establish in human studies,
F I G U R E 1 Simple diagram showing complex interaction between
meniscus tear, degeneration, and osteoarthritis (OA). Meniscus tear
and degeneration both often lead to OA over a course of years.
New evidence suggests that OA also contributes to meniscus
degeneration and likely increases the susceptibility to a meniscus
tear. A meniscus tear may precede meniscus degeneration or vice
versa. Moreover, the presence of a number of confounding factors
(listed in Table 1) further complicates this interaction
6 | RAI ET AL.

T A B L E 2 Biological processes and pathways altered in meniscus injury and degeneration

Process/Pathway Gene/protein involved Comparison Tissue Method Condition Reference

Inflammation ↑ IL‐6, TNFα Injured vs non‐injured sites Human meniscus ELISA APM Ogura et al78
↑ IL8, CXCL6, MMP3; Traumatic vs degenerative Human meniscus Real‐time APM Brophy et al79
↓ COL1A1 PCR
↑ IL‐10, IL‐6, TNFα, IL‐8 Chondral changes vs control Human synovial ELISA APM Bigoni et al12
fluid

Adipokines ↑ ADIPOQ, RETN Degenerative changes Human meniscus Real‐time APM Brophy et al60
on X‐rays PCR

Autophagy ↓ ATG‐5, LC3 Meniscus degeneration Murine meniscus IHC DMM Meckes et al51
↑ BECN1, CASP3 Medial vs lateral meniscus Lapine meniscus Real‐time Arthrotomy Heard et al80
PCR

Abbreviations: ADIPOQ, adiponectin; APM, arthroscopic partial meniscectomy; ATG ‐5, autophagy related 5; BECN1, beclin 1; CASP3, caspase 3;
COL1A1, collagen type I alpha 1; CXCL6, C‐X‐C motif chemokine ligand 6; DMM, destabilization of medial meniscus; ELISA, enzyme linked
immunosorbent assay; IL, interleukin; IHC, immunohistochemistry; LC3, light chain 3; MMP, matrix metalloproteinase; PCR, polymerase chain reaction;
RETN, resistin; TNF, tumor necrosis factor.

particularly since obtaining suitable control knees may be practically
impossible and/or unethical. It is also unlikely that tissue will be
available immediately after the meniscal injury. There have been
attempts to study meniscus tears from clinically asymptomatic
patients; however, there are obvious practical and ethical challenges in
collecting meniscus tissue from asymptomatic individuals, even though
35,75,93
meniscus tears are common in asymptomatic individuals.
Ideally, a comparison between normal uninjured meniscus and a torn
or degenerated meniscus is required to determine if the biology of
menisci truly differs between the two conditions. However, harvesting
of “intact” meniscus from an asymptomatic knee is obviously not
possible for ethical reasons. Normal meniscus may be accessible
from deceased donors, but a variety of factors such as the nature of
injury/disease causing death, the presence or absence of systemic
inflammatory or autoimmune disorders, and acute or chronic exposure
to medications make it difficult to be sure whether this tissue is a
reliable surrogate for a truly intact healthy meniscus.
6 | S T R A T E GI E S T O O V E R C O M E B A R RI E R S
I N H U M A N ME N I S C U S R E S E A R C H AR E
EMERGING
More clinical and translational studies are needed to better
understand the circumstances under which meniscal injury leads to
the initiation and or furthers the progression of knee OA. While
there have been a number of studies recently that attempt to inform
45,55,60,66,79,94,95
this question, two challenges make it particularly
difficult. First, a wide range of factors such as age, BMI, activity level,
and concomitant injury can influence meniscal injury biology and the
subsequent development of OA, making it necessary to recruit large
numbers of patients to account for these covariates. Second, OA
takes years if not decades to develop a following meniscal injury,
requiring relatively long follow up to document the development
and progression of OA. The first barrier can be overcome with
collaborative efforts to recruit larger cohorts of patients across
different providers and locations. The second barrier requires more
sensitive yet noninvasive means of detecting early joint degeneration
such as cartilage sensitive magnetic resonance imaging or more
specific serum biomarkers. Advances in both of these areas may
facilitate future studies aimed at more precisely understanding
the impact of the meniscal injury on the knee.
7 | WH AT MIGH T WE L EARN F ROM USIN G
MOUSE M O DE LS TO S TUDY THE R OLE O F
MENISCAL INJURY IN THE DEVELOPMENT
OF KNEE OA?
Currently missing from our understanding of the impact of meniscus
injury on OA is knowledge of the events set in motion by meniscus
trauma that drives subsequent articular cartilage degeneration.5 The
similarities of joint structure and biology, combined with a vast array
of genetic and proteomic tools, have led investigators to use the
mouse to study joint injuries and examine articular cartilage
pathogenesis.96 Mice have become an increasingly popular model
system for the study of posttraumatic OA. Current mouse models of
meniscus injury that progress to knee OA include destabilization of
the medial meniscus (DMM), meniscal ligament injury (MLI), and
medial meniscus tear (MMT). In each, disruption of meniscus function
directly affects knee biomechanics, compromising multiple joint tis-
sues, most prominent of which is the knee articular cartilage. It is
important to note that mouse knee biomechanics are not
identical to those of humans and the differences that exist may affect
the pathophysiological processes leading to OA. This is also true for
the tissue components making up the knee joint; mouse articular
cartilage is much thinner than human articular cartilage and the
mouse meniscus undergoes ossification during tissue maturation,
unlike the human meniscus. Last, but not least, mouse meniscus
biology (in health and disease) does not necessarily represent human
meniscus biology (in health and disease) as animal findings do not
always translate to humans. These differences should be considered
RAI ET AL.
when interpreting data obtained from meniscus injury post‐traumatic
OA models and balanced against the ability to perform mechanistic
studies through genetic manipulation in mice.
7.1 | Relationship of biomechanical and biological
changes in the development of OA
Structure‐function studies have clearly established that disruption of
the complex meniscus extracellular matrix network negatively affects
joint biomechanics and joint function. However, analyses of meniscal
injuries in humans and large animals strongly indicate that the in-
complete meniscal tears that are common in patients do not sig-
nificantly alter meniscus biomechanics at the time they occur, but often
result in the development of knee OA decades later. Injured meniscus
secretes a variety of factors including activated MMPs, and damage‐
associated molecular patterns.84 Brophy et al79 reported that meniscal
tissues from traumatic tears show much greater expression of chemo-
kines and degradative enzymes including interleukin 8, C‐X‐C motif
chemokine ligand 6, MMP‐1, and MMP‐3 that have been implicated in
articular cartilage degradation. However, it is difficult to establish a
direct cause and effect relationship due to the variable nature of the
meniscus injury, the differences in time from injury to when the sample
is taken, the specific site within the meniscus where the specimen was
taken from and the overall health status of each individual with an
injured meniscus. Availability of a mouse model of meniscus injury that
progresses to knee OA would allow for the study of the complex re-
lationship between meniscus injury and OA without having to
determine how differences in age, sex, injury site, time postinjury, and
health status influence data interpretation.
7.2 | Why meniscal injuries exhibit failed healing
responses?
How tissue regeneration programs are triggered after an injury is an
emerging research focus due to the availability of new technologies
that allow for interrogation of injury on a genome‐wide level.97 In
mammals, tissue regeneration ability is organ‐specific and
age‐dependent. The use of mouse models has been transformative in
resolving key mechanisms of tissue repair allowing investigators to
ablate specific cell types, map cell lineages, track cell progeny after
tissue injury, and perform bulk and single‐cell RNA‐sequencing.98
Recent results in mice suggest the number of genes that are
exclusively dedicated to tissue regeneration will be limited, and
large‐scale repurposing of genes with functions in embryonic
development will drive the regeneration response after injury.98 This
paradigm can be observed during bone repair where the regenera-
tion process mimics many aspects of skeletal development and many
developmental genes are reactivated upon injury in the same tem-
poral and spatial patterns.99 With respect to meniscus regeneration,
no information in the current literature focuses on the genes that
direct meniscal morphogenesis in any species other than the mouse,
| 7
leaving us unable to compare meniscus injury events to meniscus
development events in a species other than mice.100
While mice are considered to be a great resource for OA
research due to the ability to study the function of single gene, and
mouse meniscus injury models that induce OA such as DMM, MLI,
and MMT are popular among the scientific community, direct
comparison between human and mouse meniscus has limitations, as
described above. One area where mouse meniscal injury models will
be valuable is the comparison between tissue morphogenesis during
development and tissue regeneration after injury.
Studies that exist for mouse meniscus morphogenesis are largely
incomplete. Once completed, they should provide us with the
knowledge of the genes that are activated during meniscal
development, allowing us to ask whether these genes are reactivated
after injury, to uncover the signaling pathways that initiate this
process, and to investigate the ability of therapeutic agents to
enhance signaling pathways associated with meniscal morphogenesis
thereby enhancing meniscus healing.
8 | C O N CL U S I O N
The meniscus is a key tissue in the knee, performing a diverse range
of functions necessary to maintain optimal knee joint function and
homeostasis. The functional diversity of the meniscus is derived from
its structural and cellular diversity, and our lack of understanding of
the intricacies of meniscus biology are major reasons why the current
treatment of meniscus injuries is only partially successful. A number
of intrinsic (age, sex, genetics, and body weight) and extrinsic (nature,
time, and pattern of injury and degeneration) factors influence
meniscus homeostasis, repair and injury response. As meniscus
injuries often lead to OA over the long term, evaluating the
relationship between meniscus injury and OA is difficult. Although
efforts have now been directed toward the study of molecular and
cellular level changes that occur with a meniscus injury, degenera-
tion, and regeneration, identification of specific molecular pathways
that underlie the meniscus injury response and the cellular
mechanisms they influence are missing in the current literature.
While transcript‐level data on meniscus injury, degeneration, and
regeneration exist, these are difficult to validate in the absence of
patient‐matched non‐injured control tissues. As similarities exist
between human and mouse knee joint structure and function,
investigators have begun to use cutting‐edge genetic and genomic
tools to examine the usefulness of the mouse as a model to study the
intricate relationship between meniscus injury and OA.
AC KNO WL EDG M EN TS
The publications cited from the author's laboratories were partially
supported by the National Institutes of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS) of the National Institutes of Health (NIH)
grants R00 AR064837 and P30 AR074992. The content is solely the
responsibility of the authors and does not necessarily represent the
official views of NIAMS or the NIH.
8 |
CO NFLICT OF I NTERE STS
The authors declare that there are no conflict of interests.
A UT HO R C ONT RI BU TIO NS
MFR, RHB, and VR contributed to the idea and subject matter of this
review article. All authors drafted and substantially revised the
manuscript. All authors have read and approved the final submitted
manuscript.
OR CID
Muhammad Farooq Rai http://orcid.org/0000-0003-4826-4331
Robert H. Brophy http://orcid.org/0000-0002-2912-8265
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How to cite this article: Rai MF, Brophy RH, Rosen V.
Molecular biology of meniscus pathology: Lessons learned
from translational studies and mouse models. J Orthop Res.
2020;1–10. https://doi.org/10.1002/jor.24630