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Reyes Hinojosa2019
Reyes Hinojosa2019
PII: S1382-6689(19)30090-0
DOI: https://doi.org/10.1016/j.etap.2019.103219
Article Number: 103219
Reference: ENVTOX 103219
Please cite this article as: Reyes-Hinojosa D, Lozada-Pérez CA, Zamudio Cuevas Y,
López-Reyes A, Martı́nez-Nava G, Fernández-Torres J, Olivos-Meza A, Landa-Solis C,
Gutiérrez-Ruiz MC, Rojas del Castillo E, Martı́nez-Flores K, TOXICITY OF CADMIUM IN
MUSCULOSKELETAL DISEASES, Environmental Toxicology and Pharmacology (2019),
doi: https://doi.org/10.1016/j.etap.2019.103219
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Corresponding author:
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1
Synovial Fluid Laboratory. National Institute of Rehabilitation “Luis Guillermo
Ibarra Ibarra” Calzada Mexico-Xochimilco 289, C.P. 14389, Mexico City, Mexico
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Phone: +52 55 59991000, ext. 19501
2
Rheumatology Service, National Institute of Rehabilitation “Luis Guillermo Ibarra
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Ibarra”. Mexico City, Mexico
3
Orthopedic Sports Medicine and Arthroscopy Service, National Institute of
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Rehabilitation “Luis Guillermo Ibarra Ibarra”. Mexico City, Mexico
4
Tissue Engineering Cell Therapy and Regenerative Medicine Unit, National
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City, Mexico.
6
Laboratory of Experimental Medicine, Unit of Translational Medicine, Institute of
Biomedical Research, UNAM. National Institute of Cardiology “Ignacio Chávez”.
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7
Departament of genomic medicine and environmental toxicology. Institute of
Biomedical Research, UNAM. Mexico City, Mexico.
Email: karinabiologist@hotmail.com
Epidemiological studies have reported that exposure to toxic metals like cadmium
(Cd) may promote the development of musculoskeletal diseases, such as
osteoporosis, rheumatoid arthritis (RA), and osteoarthritis (OA), among others. The
objective of this review is to summarize the molecular mechanisms of inflammation
and oxidative stress activated by Cd at the bone level, particularly in osteoporosis,
RA, and OA. Cadmium can increase bone resorption, affect the activity of
osteoclasts and calcium (Ca) absorption, and impair kidney function, which favors
the development of osteoporosis. In the case of RA, Cd interferes with the activity
of antioxidant proteins, like superoxide dismutase (SOD) and catalase (CAT). It
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also promotes an inflammatory state, inducing the process of citrullination, which
affects the proteins of immune response. On the other hand, accumulation of Cd in
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the tissues and blood of smokers has been related to the development of some
musculoskeletal diseases. Therefore, knowing the negative impact of Cd toxicity at
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the articular level can help understand the damage mechanisms it produces,
leading to the development of such diseases.
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Introduction
Cadmium (Cd) is a heavy metal and one of the most toxic metals, classified as a
category I carcinogen by the International Agency for Research on Cancer. Its
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impact on health was first recorded prior to World War Two, in the form of the
condition known as „Itai-itai‟ (Japanese; „it hurts it hurts‟). It was not until the late
1960‟s that the metal was conclusively associated with this condition and an
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epidemiologic study carried out in 1967 and 1968 revealed that zinc (Zn) mining
near the Jinzu River in the Toyama Prefecture, Japan was responsable for the
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cadmium pollution. Toyama is located on the northeast coast of the main island of
Japan. The metal contaminated the Jinzu River, wich irrigates approximately 20
km2 of rice fields through several channels primarily affecting women whose
subsistence depended on those fields. Itai-itai, is the most severe from of chronic
Cd poisoning, clinically characterized by kidney damage in the form of glomerular
and tubular dysfunction resulting in proteinuria, osteomalacia, and osteoporosis,
with back and femoral pain gradually extending to the rest of the body for several
years until the patient is bed-ridden due to bone fractures. Twenty new cases of
the Itai-itai disease were diagnosed as late in the year 2000, which were
acknowledged by the government of Toyama. These cases reflect the long-term
environmental exposure to cadmium and the impact of this metal at the kidney and
bone level (Nishijo et al., 2017; Aoshima K, 2016; Baba et al., 2014; Inaba et al.,
2005).
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well as the combustion of fuels that produce gases and suspended particles,
tobacco smoke, use of fertilizers and paint additives (Torres-Sánchez et al., 2018;
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Rodríguez & Mandalunis, 2018; IARC, 2012; Bhattachaiyya, 2009). Exposure to
this metal can be acute or chronic, mainly due to ingestion of food or inhalation of
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cigarette smoke as the main sources. Tobacco has been reported to accumulate
high concentrations of Cd in a range between 0.77 - 7.02 μg/g (Xiong et al., 2019;
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Hutchinson, 2015). It is estimated that over 80% of ingested Cd comes from
cereals, primarily rice and wheat (Pérez & Azcona, 2012). Cadmium absorption in
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lungs, testicles, and bones. In the liver, Cd binds to small peptides, such as
glutathione (GSH), or proteins with low molecular weight, like metallothionein (MT),
and these complexes are slowly secreted in the bile or released to the
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an in vivo model that the acute intraperitoneal administration of Cd at a
concentration above 5 mg/L induces changes in bone mineral density (BMD), as
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the organic and mineral contents of the bone decrease due to an increase in bone
resorption. It is suggested that the primary damage mechanism of Cd is through
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direct inhibition of bone formation, as well as stimulation of bone resorption,
influencing the activity of osteoblasts and osteoclasts and replacing Ca in the
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hydroxyapatite crystals.
On the other hand, it has also been proposed that oxidative stress (OS) may play a
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significant role in the development of osteoporosis (Choi & Han, 2015; Shutte et
al., 2008). Reactive Oxygen Species (ROS) are known to be involved in the bone
remodeling process, as the excessive generation of ROS by the osteoclasts boosts
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hydroxyl radical (.OH) (Brzóska et al., 2011). Smith et al. (2009) reported in an in
vitro model with Saos-2 osteoblastic cells that Cd increases ROS formation and
lipoperoxidation through GSH depletion. Likewise, it has been suggested that Cd-
induced OS damages osteoblasts by decreasing the expression of the runt-related
transcription factor 2 (RUNX2) mRNA, which is a critical mediator in bone
formation and in osteoblast differentiation and function; it also regulates the
expression of bone matrix proteins, like type I collagen (Col I) and osteocalcin.
Murphy et al. (2016) reported that Cd exposure through different sources, mainly
tobacco smoke, is significantly associated with several pathologies, such as RA, as
it is considered a potential citrullination agent through calcium channels, a process
that promotes loss of the immune system tolerance (Murphy et al., 2016;
Hutchinson, 2015). It has been observed that, during the osteoporosis process,
acute exposure to Cd can significantly increase the area and perimeter of the
Haversian canals as a consequence of demineralization (Martiniaková et al.,
2011). However, in vivo studies have shown that an acute dose of 0.5 mg CdCl 2/kg
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of body weight three times a week does not significantly affect femur length or
body weight, nor does it affect lacunar resorption and/or osteoporotic fractures, so
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a single Cd dose for 36 hours would not be enough to cause osteoporosis.
Regarding the relation of Cd with OA development, Attia et al. (2014) report that
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exposure to Cd through tobacco smoke can contribute to OA development.
Nevertheless, the role of Cd in OA pathogenesis has yet to be fully elucidated.
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The objective of this review is to present updated evidence on the articular damage
mechanisms by Cd as main axis in the development of rheumatic diseases, such
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Osteoporosis
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At the bone level, Cd concentrations between 10 and 100 nM have been reported
to have a deleterious effect, as they decrease BMD by inducing an increase in
bone resorption and promoting osteoclast formation. Furthermore, it directly affects
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the levels of trace elements, particularly Ca and Zn, which are constituent parts of
bone tissue. Chen et al. (2013) demonstrated in an in vivo model of 8-week old
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male Sprague-Dawley rats that a CdCl2 intake of 50 mg/L for 24 hours significantly
decreases BMD (by 10%) and trabecular thickness; they also observed an
increase in intratrabecular space and up to 94% of active osteoclasts in
comparison to the non-treated group. Finally, they reported a positive expression of
the receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG),
proteins related to osteoclast differentiation, in osteoblasts and chondrocytes.
In a study of smokers occupationally exposed to the metal in residual plants, Taha
et al. (2018) found a significant increase of Cd in serum and urine, as well as an
elevated concentration of OPG when compared to non-exposed smokers.
Moreover, they found a significant increase in bone pain percentage compared to
non-exposed smokers (95% vs. 37.7%). These findings conclude that a long-term
exposure to Cd has an osteotoxic effect resulting in bone tissue loss. Sughis et al.
(2011) determined the urine concentration of Cd and deoxypyridinoline (DPD) as
bone resorption marker (because it is a type 1 collagen binding protein of the bone
extracellular matrix), and found a higher concentration in girls than in boys from the
metropolitan area of Pakistan, reporting Cd values of 0.65 nmol/mmol of creatinine
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vs. 0.41 nmol/mmol of creatinine and DPD values of 216 nmol/mmol of creatinine
vs. 83.5 nmo/mmol of creatinine, respectively. The authors associated urinary Cd
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with high DPD excretion, suggesting that the bone demineralization effect of Cd
takes place at relatively low environmental concentrations and at an early age, with
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the clinical consequences appearing in adult life, as Cd can remain in the body
from childhood through adulthood.
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Xiao Chen et al. (2009) proved that Cd exposure through ingestion of
contaminated rice affects BMD. The sourcing area of the rice was classified as a
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highly contaminated area if it was within 0.5 km from the smelters and the Cd
concentration of rice was 3.7 mg/kg, and as a moderately contaminated area if it
was within 12 km from the smelters and the Cd concentration of rice was 0.51
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mg/kg. They found that the relative and absolute change in BMD decrease is
related to the Cd exposure increase. Regarding the highly contaminated area, they
point out that changes in BMD were positively correlated to concentrations of urine
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Cd (UCd) and blood Cd (BCd) and the menopause period, in addition to age,
height, and weight in men. Finally, osteoporosis prevalence increased in relation to
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the UCd and BCd levels in the highly exposed group, both in men and women.
Subsequently, the same research group (Xiao Chen et al., 2013) used
concentrations of UCd and BCd as biomarkers of exposure to demonstrate that Cd
induces osteoporosis, finding BCd levels in a range between 1.39 ug/L - 2.38 ug/L,
and UCd levels between 3.78 ug/g of creatinine - 6.36 ug/g of creatinine; these
values are close to the benchmark associated with kidney effects reported by WHO
(5.0 ug/g of creatinine).
On the other hand, they report Cd levels associated with a lower bone mass to be
between 0.72 ug/L - 1.35 ug/L (blood) and between 2.14 ug/g - 3.99 ug/g of
creatinine (urine). Finally, the data suggests that BMD is related to the presence of
Cd in blood, resulting in osteoporosis, and urine Cd is associated with a decreased
bone mass.
Nambunmee et al. (2010) reported high levels of Cd in the rice from the Mae Sot
District in Thailand, with a range of 0.5 to 7.7 mg/kg, in contrast to the minimum
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allowable value of 0.2 mg/kg, and above the level considered safe for food, which
is 0.1 mg/kg. This study related chronic exposure to elevated dietary Cd
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concentrations to an increased risk of osteopathy, particularly Ca resorption, renal
tubular dysfunction, and bone resorption acceleration. The authors report blood Cd
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levels in individuals chronically exposed through consumption of contaminated
food between 1.44 - 28.65 ug/L (men) and 0.80 - 33.12 ug/L (women). They also
evaluated the serum osteocalcin in women with fracture risk as bone formation
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marker, and deoxypyridinoline and N-terminal telopeptide of type 1 collagen (NTx)
as bone resorption markers. The deoxypyridinoline values in those women
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averaged >7.6 nmol/mmol of creatinine and the NTx values averaged >54.3 nmol
of BCE/mmol of creatinine, both above the expected values for this study group.
Moreover, the levels of both bone markers showed a negative and positive
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Cd exposure, as well as a fast bone resorption among people with high urinary Cd
excretion values >10 μg/g of creatinine. These results suggest that dietary chronic
exposure to Cd causes an imbalance at the bone level, impacting the tubular renal
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function and bone metabolism, which is due to an increase in Ca release and bone
metabolism markers related to the Cd exposure level.
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tissue of OA patients.
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Cd/L for 12 months causes a decrease in total BMD; both the bone mineral content
and the BMD decreased at the vertebral level. The same effect was observed at
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the femur level, determining the presence of osteopenia and osteoporosis. The
concentration in urine of the C-terminal telopeptide of type 1 collagen (CTx)
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increased by 78% in the rats treated with Cd, and the serum level increased by
57%. They observed that the activity of alkaline phosphatase (ALP) decreased at
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the cortical bone and trabecular level by 44% and 54%, respectively, whereas Ca
excretion in serum and urine increased by 80%. Urine Cd concentration gradually
increased to a range between 0.665 - 2.498 μg/g of creatinine compared to the
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control group, which showed a range of 0.197 - 0.466 μg/g of creatinine; likewise,
blood Cd concentration increased to 0.793 + 0.035 μg/L in contrast to the control
group, which had an average value of 0.470 + 0.043 μg/L. Finally, the authors
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in addition to Ca being unable to fix itself to the bone structure. Therefore, they
concluded that Cd is a major risk factor for osteoporosis development, even at low
exposure levels throughout life.
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Rheumatoid Arthritis
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Rheumatoid arthritis is a chronic inflammatory disease caused by genetic,
reproductive, and environmental factors (Turk et al., 2014). One of the
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environmental factors that have been associated with RA development is smoking
(Muphy et al., 2016; Van de Stadt et al., 2011). Recent studies show that smoking
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cigarettes can be the external trigger for asymptomatic individuals with a genetic
predisposition to develop RA (Sugiyama et al., 2010). Tobacco use is the most
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clearly defined risk factor for seropositive RA, as it is a strong stimulus for the
citrullination that involves post-translational changes of proteins to cyclic
citrullinated peptide antibodies (anti-CCP), resulting in the loss of tolerance of the
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to individuals who have never smoked and former smokers, the latter having a risk
that lingers for at least 20 years. This evidence suggests that the toxin (Cd)
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responsible for RA development may remain in the body for at least 2 decades.
Tobacco is considered the main Cd exposure source among smokers, who may
have blood Cd levels up to three times higher than non-smokers. At the tissue
level, it has been proved that the lungs of former smokers go back to their basal
level of Cd only after 21 or 22 years of abstinence (Afridi et al., 2011).
In 2015, the group of Ansari described in a RA animal model that a dose of 50 ppm
of cadmium chloride (CdCl2) induces a severe inflammation associated with
edema, flow of polymorphonuclear cells, degradation of cartilage, and restriction of
movement in the paws. They also observed a decrease in the activity of
superoxide dismutase (SOD) and CAT, as well as an increase in lipoperoxidation,
the levels of nitric oxide (NO), and expression of the NF-Kβ transcription factor,
which is related to inflammation and OS response.
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was higher in smoking RA patients than in the other groups included in the study.
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Later, Afridi et al. (2012) showed that the average concentration of Cd and Pb in
hair samples of smoking and non-smoking RA patients from Pakistan were
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significantly higher when compared to a control group of Irish patients (5.86 ± 0.63
µg/g of Cd and 4.59 ± 0.51 µg/g of Pb, respectively). Likewise, Zn concentration
was lower in the samples of these patients. This shows that the Zn deficiency and
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the high exposure to Cd y Pb as a consequence of tobacco use can be synergic
risk factors associated with RA development.
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(26 smokers and 26 non-smokers). They found that Cd levels were higher in the
blood and hair samples of the RA patients than the controls, and the difference
was significant for smoking patients.
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induced RA development. Elastase and lipid peroxidation at the joint level were
found to increase in the rats receiving a CdCl2 dose of 50 ppm, as well as the NO
levels, in contrast to the rats who received lower doses. On the other hand, the rats
that received a dose of 5 ppm had higher levels of SOD and CAT, enzymes that
neutralize or offset the effects of free radicals. Regarding histopathological
changes, the rats that received a CdCl2 dose of 50 ppm had a diffuse flow of
polymorphonuclear cells to the synovial membrane, degradation of cartilage, and
higher production of TNFα and IL-6. This evidence suggests that exposure to
CdCl2 during the induction phase of CIA nullifies the development of the disease,
whereas it exacerbates it at higher doses.
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to have a significant affinity to being absorbed by the synoviocytes of RA and OA
patients. Moreover, the presence of Zn reduced the intracellular content of Cd.
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Cytokine treatment increased Cd absorption, even in the presence of Zn. In the
absence of cytokines, the absorption rate was low when exposed to Zn, in contrast
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to those only exposed to Cd with 20% more absorption. Expression of the Zn
transporter (ZIP-8) and metallothionein-1 isoforms (MT-1s), as well as the ratio of
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metalloproteinase-3 (MMP-3) to metalloproteinase inhibitor TIMP-1 (MMP-3/TIMP-
1) were also evaluated. The metal importer increased with exposure to IL-17/TNF-
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α by increasing expression of ZIP-8, unlike exposure to Zn, which did not modify
the expression of that transporter, whereas exposure to Cd did reduce it
significantly. Expression of MT-1s in the presence of Cd increased 50 times
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compared to the RA and OA synoviocytes that were only exposed to Zn. On the
other hand, Zn decreased expression of MT-1 when compared to those exposed to
Cd, playing a major role in detoxification of Cd and subsequently of its intracellular
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Osteoarthritis
The relationship between OA and Cd has not been extensively studied because
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little is known about the composition of the elements in the bone and/or the
correlation between the metals in the cartilage and bones of osteoarticular
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degeneration patients depending on the exposure type (occupational, residential,
smoking).
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Wiechula et al. (2008) reported that Pb and Cd concentrations in the femoral head
of patients with coxarthrosis is approximately 3 mg/kg and 0.07 mg/kg,
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respectively, but it is higher in knee OA patients. The concentration of Cd in the
cortical bone and the femoral head of coxarthrosis patients is similar to the
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Ni) in different parts of the knee joint in patients who underwent joint replacement
surgery. They demonstrated a significant difference in Cd content between male
and female OA patients in the tibia (0.016 mg/kg in men vs. 0.014 mg/kg in
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women), femur (0.017 mg/kg in men vs. 0.013 mg/kg in women), and meniscus
(0.008 mg/kg in men vs. 0.007 mg/kg in women), taking into account that the
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They evaluated the relationship between blood Cd levels in smoking patients and
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OA severity in a different study and identified a higher percentage of patients with
moderate and severe OA in the smoker group: 61.6%. The differences they found
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in Cd levels (8.98 + 1.09 μg/dL in smokers vs. 0.50 + 0.66 μg/dL in the control
group) led them to conclude that the presence of Cd as toxic element in tobacco
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can contribute to a higher risk of cartilage loss and a more severe OA development
in symptomatic OA patients, in contrast to non-smokers (Attia et al., 2014).
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Our group has found in a 3D culture of human chondrocytes at an acute exposure
to 5 μM of CdCl2 for 12 hours that Cd can promote the expression of enzymes
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Knowing the impact of Cd toxicity at the molecular level in connection with articular
damage is critical in order to include provisions addressing this in healthcare and
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of dry weigh and 5 ng/m3 at the air level. Regular intake rates of Cd in cereals and
other vegetables are around 2-25 μg/day among children and range from 10 to 50
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μg/day in adults, with the highest values found in areas with industrial activities
related to Cd (Bhattacharyya, 2009).
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Furthermore, the European Commission appointed a group of scientists to
evaluate the health risks of Cd. The group determined the exposure range to be
between 1.9 and 3.0 μg/kg of body weight per week (average of 2.3 μg/kg) among
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the general population, i.e., the median intake is very close to the provisional
tolerable weekly intake (PTWI). Using urinary β2-microglobulin as a marker for
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Based on studies in animals, the Agency for Toxic Substances and Disease
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Registry (ATSDR) has determined the minimum risk levels to be 0.03 μg Cd/m 3
and 0.01 μg Cd/m3 for acute and chronic inhalation, respectively. And a value of
0.1 μg Cd/kg/day for chronic oral intake, as well as a reference dose value of 5x10 -
4
mg/kg/day in water and 1x10-3 mg/ (kg.day) in food to avoid reaching a value of
200 μg/g at the kidney level (Thévenod & Lee, 2013; ATSDR, 2008).
The German Commission on Human Biological Monitoring evaluates reference
levels of 1.0 μg Cd/L of blood and 0.8 μg Cd/L of urine among non-smokers
between 18 and 69 years old. Smokers show high values of 3.32 μg Cd/L of blood
and 1.20 μg Cd/L of urine. Occupational exposure also results in high Cd levels in
blood and urine. Workers exposed to CD in a non-ferrous foundry showed average
levels of 6.23 μg Cd/g of creatinine (range of 0.87-165 μg/g creatinine) and 6.54 μg
Cd/L of blood (range of 1.6-51 μg/L). Using an array of early markers of kidney
damage within a dose-response, early effects at concentrations between 0.5 and 3
μg Cd/g creatinine have been identified in general populations (Thévenod & Lee,
2013).
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Lastly, Sughis et al. (2011) reported that children exposed to low environmental
concentrations of Cd have been associated with bone resorption evidence,
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suggesting direct osteotoxic effects with calciuria. These findings could have a
clinical relevance when such populations reach a later age. Bhattacharyya (2009)
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reports that Cd may directly act on bone cells, as it reduces bone formation and
increases bone resorption in organ culture and bone cells systems. Even at a
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concentration of 1 ng Cd/mL, it is directly within the range of Cd concentration in
blood of those people exposed to environmental agents, such as tobacco smoke.
This demonstrates that even at low environmental exposure levels, Cd has
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adverse health impacts, directly affecting the bones, favoring skeletal integrity loss,
increasing fracture risk, and at the cartilage level, promoting cartilage loss, as
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Conclusion
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Cadmium is a highly toxic metal to which human beings are exposed through
different sources, such as batteries, tobacco smoke, and contaminated food, like
cereals. Due to its intrinsic characteristics and the widespread distribution of the
exposure sources, Cd contributes to the development of several diseases, such as
osteoporosis (inhibiting bone formation) (Figure 1), RA (affecting the citrullination
process, leading to loss of tolerance of the immune system) (Figure 2), and OA
(the role it plays in this disease is not very well known yet, and only its presence in
blood has been related to the severity degree. The findings of our group reveal the
potential molecular pathway it triggers) (Figure 3). Therefore, understanding the
molecular mechanisms through which Cd promotes the development of
musculoskeletal diseases is paramount in order to find therapeutic targets, take
prevention measurements for handling this metal and support consumption of
healthy foods rich in antioxidants,
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Van de Stadt LA, de Koning MH, van de Stadt RJ, et al. 2011. Development of the
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increasing the bone resorption activity of the osteoclasts.
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Figure 2. Molecular mechanism of Cd in rheumatoid arthritis. By decreasing
the anti-oxidative response, its pro-oxidative mechanism favors the inflammatory
response through TNF-α, which activates the macrophages. It also promotes
production of citrullinated antipeptides that activate B and T lymphocytes. T cells
interact with dendritic cells, increasing the chronic inflammatory response that
promotes the activation of the molecules related to cartilage degradation through
macrophages.
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Figure 3. Signaling pathway of Cd in osteoarthritis. It promotes the generation
of reactive oxygen species (ROS), like the hydroxyl radical (O2.-) and hydrogen
peroxide (H2O2), leading to production of IL-1β and IL-6, which activate the
metalloproteinases (MMPs) that damage the extracellular matrix.
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