Chondrocyte death by apoptosis is associated with the initiation and severity of articular cartilage degradation

Aim: To investigate the role of chondrocyte apoptosis in the initiation and severity of articular cartilage (AC) damage. Methods: Articular cartilage from equine metacarpophalangeal (MCP) (n = 13) and metatarsophalangeal (MTP) (n = 16) joints was used and each graded macroscopically for cartilage degradation (macroscopic osteoarthritis [OA] grade). Cartilage was sampled from six regions on the articular surface of both joint types and graded using a ‘modified’ Mankin scoring system. Apoptosis of chondrocytes in cartilage sections was assessed by expression of active caspase‐3 using indirect immunohistochemistry. Results: Apoptosis was found to increase significantly with macroscopic OA grade (P < 0.0001). There was a significant trend for increasing ‘modified’ Mankin score with increasing macroscopic OA grade (P < 0.0009). Apoptosis was significantly higher in the superficial zone than in the middle or deep zones (P < 0.01 and P < 0.001, respectively). The incidence of apoptosis correlated significantly with the early stages of microscopic cartilage damage (‘modified’ Mankin scores 0–3). Significant differences in overall apoptosis were noted when cartilage specimens with a ‘modified’ Mankin score of 3 were compared to grade 2 (P < 0.001), grade 1 (P < 0.001) and grade 0 (P < 0.05) specimens. However, no significant difference in overall apoptosis was noted between grade 3, 4 and 5 samples. Conclusions: The positive correlations of chondrocyte apoptosis with early stages of OA and severity of cartilage damage in the joints, suggest that this process is intrinsically linked to cartilage damage and may be associated with the initiation of cartilage degradation in OA.     

The effect of cartilage degeneration on ultrasound speed in human articular cartilage

Objectives: We investigated the effect of cartilage degeneration on ultrasound speed in human articular cartilage in vitro.

Methods: Ultrasound speed was calculated by the time-of-flight method for 22 femoral condyle osteochondral blocks obtained from osteoarthritis patients. In parallel, histological evaluation of specimens was performed using the modified Mankin and OARSI scores.

Results: The mean ultrasound speed was 1757?±?109 m/s. Ultrasound speed showed significant negative correlation with OARSI score, and a decreasing tendency with high Mankin scores. Good correlation was found between the optically measured and the calculated cartilage thickness.

Conclusion: Our results show that articular cartilage degeneration has relatively little influence on ultrasound speed. In addition, morphological evaluation of articular cartilage using a preset value of ultrasound speed seems to offer relatively accurate results.     

Lifelong voluntary joint loading increases osteoarthritis in mice housing a deletion mutation in type II procollagen gene,and slightly also in non-transgenic mice

Objectives: To investigate the effects of voluntary running on the incidence and severity of osteoarthritis (OA) and associated changes in cartilage matrix and subchondral bone in a transgenic Del1 mouse model for OA.

Methods: Del1 mice and their non-transgenic littermate controls were housed from the age of 5–6 weeks to 15 months in individual cages with running wheels. The running activity of each mouse was monitored for the entire 12 month period. Additional Del1 and control mice were housed in individual cages without running wheels. At the end of the experiment the severity of OA was evaluated by light microscopy, and the articular cartilage matrix changes by digital densitometry and quantitative polarised light microscopy.

Results: Lifelong voluntary running increased the incidence and severity of OA significantly in Del1 mice (transgenic runners), and slightly also in non-transgenic runners. Severe OA changes increased from 39% in transgenic non-runners to 90% in transgenic runners (p=0.006) in lateral tibial condyles, and from 24% to 80% (p=0.013) in lateral femoral condyles, respectively. The proteoglycan content of articular cartilage was reduced in transgenic runners in comparison with transgenic non-runners (p=0.0167), but a similar effect was not seen in non-transgenic runners compared with non-transgenic non-runners. No attributable differences were seen in the collagen network of articular cartilage or in the subchondral bone between any of the groups.

Conclusion: The Del1 mutation has earlier been shown to disturb the assembly of the cartilage collagen network and thereby increase the incidence and severity of OA with age. In this study, voluntary running was shown to increase further cartilage damage in the lateral compartments of the knee. This suggests that articular cartilage in Del1 mice is less resistant to physical loading than in control mice. Despite severe OA lesions in the knee joint at the age of 15 months, Del1 mice continued to run voluntarily 2–3 km every night.

     

Association of magnetic resonance imaging-based knee cartilage T2 measurements and focal knee lesions with knee pain: data from the Osteoarthritis Initiative

Objective

To evaluate the association of magnetic resonance imaging (MRI)–based knee cartilage T2 measurements and focal knee lesions with knee pain in knees without radiographic osteoarthritis (OA) among subjects with OA risk factors.

Methods

We studied the right knees of 126 subjects from the Osteoarthritis Initiative database. We randomly selected 42 subjects ages 45–55 years with OA risk factors, right knee pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain score ≥5), no left knee pain (WOMAC pain score 0), and no radiographic OA (Kellgren/Lawrence [K/L] score ≤1) in the right knee. We also selected 2 comparison groups: 42 subjects without knee pain in either knee and 42 with bilateral knee pain. Both groups were frequency matched to subjects with right knee pain only by sex, age, body mass index, and K/L score. All of the subjects underwent 3T MRI of the right knee. Focal knee lesions were assessed and cartilage T2 measurements were performed.

Results

Prevalences of meniscal, bone marrow, and ligamentous lesions and joint effusion were not significantly different between the groups (P > 0.05), while cartilage lesions were more frequent in subjects with right knee pain only compared to subjects without knee pain (P < 0.05). T2 values averaged over all of the compartments were similar in subjects with right knee pain only (mean ± SD 34.4 ± 1.8 msec) and in subjects with bilateral knee pain (mean ± SD 34.7 ± 4.7 msec), but were significantly higher compared to subjects without knee pain (mean ± SD 32.4 ± 1.8 msec; P < 0.05).

Conclusion

These results suggest that elevated cartilage T2 values are associated with findings of pain in the early phase of OA, whereas among morphologic knee abnormalities only knee cartilage lesions are significantly associated with knee pain status.     

Correlation of magnetic resonance imaging–based knee cartilage T2 measurements and focal knee lesions with body mass index: Thirty‐six–month followup data from a longitudinal,observational multicenter study

Objective

To compare magnetic resonance imaging (MRI)–based knee cartilage T2 measurements and focal knee lesions and 36‐month changes in these parameters among knees of normal controls and knees of normal weight, overweight, and obese subjects with risk factors for knee osteoarthritis (OA).

Methods

A total of 267 subjects ages 45–55 years from the Osteoarthritis Initiative database were analyzed in this study. Two hundred thirty‐one subjects had risk factors for knee OA, but no radiographic OA (Kellgren/Lawrence score ≤1) at baseline. Thirty‐six subjects were normal controls. Subjects with OA risk factors were stratified in 3 groups: normal weight (n = 78), overweight (n = 84), and obese (n = 69). All subjects underwent 3T MRI of the right knee at baseline and after 36 months. Focal knee lesions were assessed and cartilage T2 measurements (mean T2 and T2 texture analysis) were performed.

Results

The baseline prevalence and severity of meniscal and cartilage lesions were highest in obese subjects and lowest in normal controls (P < 0.05). Obese subjects had the highest mean T2 values and the most heterogeneous cartilage (as assessed by T2 texture analysis), while normal controls had the lowest mean T2 values and the most homogeneous cartilage at baseline (P < 0.05). Increased body mass index (BMI) was significantly (P < 0.05) associated with greater progression of cartilage lesions and constantly elevated cartilage T2 entropy over 36 months.

Conclusion

In preclinical OA, increased BMI is associated with more severe cartilage degeneration as assessed by both morphologic and quantitative MRI measurements.     

Hyaluronan-binding receptors: possible involvement in osteoarthritis

Abstract

Our objectives were to compare the expression of the hyaluronan receptors CD44 and RHAMM in knee synovial tissue of patients with and without advanced osteoarthritis (OA). Both receptors were detected immunohistochemically; the staining appeared more intense in the tissues from the patients with advanced OA. Expression of CD44 and RHAMM were each significantly increased (p < 0.05) in synovial tissue from patients with OA, as determined by means of Western-blot analysis. The findings suggested that changes in levels of the HA-binding proteins might be implicated in the development or progression of OA.     

The effect of low-level laser to apoptosis of chondrocyte and caspases expression,including caspase-8 and caspase-3 in rabbit surgery-induced model of knee osteoarthritis

The purpose of this study was to observe the effect of 810-nm low-level laser to apoptosis of chondrocyte and related proteins, including caspase-3 and caspase-8, in rabbit surgery-induced model of knee osteoarthritis. A total of 24 New Zealand White rabbits were randomly assigned into 3 groups: test group, model group, and normal group. The rabbits in test group and model group received anterior cruciate ligament transection in the right knee. Six weeks after transection, the rabbits in test group were given 10-session 810-nm laser illumination. Eight weeks after transection, all animal were killed. Modified Mankin Score was made for histological assessment. The caspases expressions and chondrocytes apoptosis were tested using the immunohistochemistry and TUNEL assessment, respectively. The modified Mankin Score of test group was significantly lower than model group (P < 0.01) and higher than normal group (P < 0.01). The caspase-8 expression of test group was lower than model group and higher than normal group, but no significant difference was found (P > 0.05). This study revealed that the 810-nm low-level laser can improve cartilage structure, prevent articular cartilage degradation and significantly decrease the expression of caspase-3 in this surgery-induced OA model. Further studies are needed.     

Serum levels of resistin and interleukin-17 are associated with increased cartilage defects and bone marrow lesions in patients with knee osteoarthritis

Objectives: To investigate cross-sectional associations between serum levels of resistin and interleukin-17 (IL-17) and cartilage defects and bone marrow lesions (BMLs) in patients with knee symptomatic osteoarthritis (OA).

Methods: One hundred and ninety-four consecutively-selected patients with knee symptomatic OA (mean 55.4 years, range 34–74, 87% females) were included in Anhui Osteoarthritis (AHOA) Study. Knee cartilage defects and BMLs were determined at different sites using T2-weighted fat-suppressed fast spin echo MRI. Serum resistin, IL-17, and high-sensitivity C-reactive protein (hs-CRP) levels were measured using ELISA.

Results: In multivariable analyses, serum resistin was positively associated with cartilage defects at lateral femoral, lateral tibial, and medial tibial (all p?p?2.45?pg/ml), IL-17 was positively and significantly associated with cartilage defect score at nearly all sites (ORs: 1.33–1.44, all p?p?Conclusions: Serum levels of resistin were positively and independently associated with cartilage defects and BMLs in patients with knee OA. Serum IL-17 was significantly associated with cartilage defects and BMLs in patients with an increased inflammatory status. These suggest that metabolic and inflammatory mechanisms may have a role to play in knee OA.     

Detection of intraarticular abnormalities in osteoarthritis of the knee

Objective. To determine whether intraarticular abnormalities in osteoarthritis (OA) of the knee can be detected as well by needle arthroscopy as by standard arthroscopy. Methods. Needle arthroscopy followed by standard arthroscopy was performed on 10 patients with knee OA (diagnosed according to American College of Rheumatology criteria) whose symptoms were not entirely attributable to the OA and were therefore an indication for further evaluation. Each knee was assessed for abnormalities of the menisci, articular cartilage (6 sites), and synovium (6 sites). Results. Evaluation of the 18 menisci visualized with both techniques yielded the same results: 6 abnormal and 12 normal. Among the 54 articular cartilage sites evaluable with both procedures, 16 were judged normal by both needle arthroscopy and standard arthroscopy. Of the 38 cartilage sites judged abnormal by standard arthroscopy, 34 (89%) were abnormal by needle arthroscopy. Both techniques indicated cartilage changes were the same at 42 (78%) of the 54 sites; changes at the other 12 sites were 1 grade higher by standard arthroscopy than by needle arthroscopy. Both needle arthroscopy and standard arthroscopy revealed 51 evaluable sites in the synovium. Of 34 areas judged abnormal by standard arthroscopy, 24 (71%) were also judged abnormal by needle arthroscopy; 17 areas were judged normal by both techniques. The 2 techniques assigned the same macroscopic score in 27 (53%) of 51 areas of the synovium, with a higher grade by standard arthroscopy in all but 1 of the other 16 areas. Conclusion. These pilot data suggest that in knee OA, needle arthroscopy can 1) accurately detect meniscal abnormalities, 2) detect cartilage abnormalities, but may underestimate the severity, and 3) detect most synovial abnormalities, but often underestimates the severity. Needle arthroscopy is a potentially valuable rheumatologic tool for the assessment of OA of the knee.     

The quantitation of a native chondroitin sulfate epitope in synovial fluid lavages and articular cartilage from canine experimental osteoarthritis and disuse atrophy

Objective. Previous studies have shown the presence of a native chondroitin sulfate epitope in articular cartilage proteoglycans from canine knee joints with experimental early osteoarthritis (OA), but not in normal cartilage. The objective of this study was to quantitate the native epitope recognized by monoclonal antibody 3-B-3 in synovial fluids and articular cartilage of diseased joints. Methods. An immunoassay with monoclonal antibody 3-B-3, which recognizes a native chondroitin-6-sulfate structure, was developed and used to analyze synovial fluid lavage material and extracts of articular cartilage from canine knee joints with early experimental OA or with mild disuse atrophy, and from control animals. Results. The concentration of epitope in the OA fluids was elevated 33–35-fold, and in the OA articular cartilage extracts it was elevated > 200-fold, compared with samples from the control group. No significant difference was detected in the levels of 3-B-3 epitope in the synovial fluid lavage material or cartilage extracts from the joints of the disuse group versus the control group. Conclusion. The native 3-B-3 epitope in articular cartilage and synovial fluids may be a specific marker of ongoing anabolic events in early degenerative joint disease.     

Attenuation of osteoarthritis progression by reduction of discoidin domain receptor 2 in mice

Objective

To investigate whether the reduction of discoidin domain receptor 2 (DDR‐2), a cell membrane tyrosine kinase receptor for native type II collagen, attenuates the progression of articular cartilage degeneration in mouse models of osteoarthritis (OA).

Methods

Double‐heterozygous (type XI collagen–deficient [Col11a1^+/−] and Ddr2‐deficient [Ddr2^+/−]) mutant mice were generated. Knee joints of Ddr2^+/− mice were subjected to microsurgical destabilization of the medial meniscus. Conditions of the articular cartilage from the knee joints of the double‐heterozygous mutant and surgically treated mice were examined by histology, evaluated using a modified Mankin scoring system, and characterized by immunohistochemistry.

Results

The rate of progressive degeneration in knee joints was dramatically reduced in the double‐heterozygous mutant mice compared with that in the type XI collagen–deficient mice. The progression in the double‐heterozygous mutant mice was delayed by ∼6 months. Following surgical destabilization of the medial meniscus, the progressive degeneration toward OA was dramatically delayed in the Ddr2^+/− mice compared with that in their wild‐type littermates. The articular cartilage damage present in the knee joints of the mice was directly correlated with the expression profiles of DDR‐2 and matrix metalloproteinase 13.

Conclusion

Reduction of DDR‐2 expression attenuates the articular cartilage degeneration of knee joints induced either by type XI collagen deficiency or by surgical destabilization of the medial meniscus.

     

Effects of chronic growth hormone and insulin‐like growth factor 1 deficiency on osteoarthritis severity in rat knee joints

Objective

To determine the effects of chronic deficiency of growth hormone (GH) and insulin‐like growth factor 1 (IGF‐1) on osteoarthritis (OA) severity.

Methods

Thirty‐five rats were divided into 4 treatment groups at 4 weeks of age: 1 control group (normal GH/IGF‐1 levels [heterozygous]) and 3 groups of dwarves with a genetic mutation that results in GH deficiency. The first dwarf group received GH for 64 weeks (GH replete) and the second received GH until 14 weeks of age, followed by saline for 50 weeks (adult‐onset GH/IGF‐1 deficiency [AO‐GHD]). The third dwarf group received saline injections only (lifetime GH deficient [GHD]). Sections of the medial knee joint compartment were graded and measured histologically; data were summarized using factor analysis, and treatment effects were assessed using analysis of variance and adjusting for body weight.

Results

Terminal IGF‐1 levels and body weights were significantly affected by treatment (P = 0.002 and P < 0.001, respectively). Factor analysis yielded a total of 5 factors, the first 3 of which were not significantly affected by treatment. Factor 4 (weighted by medial tibial plateau articular cartilage width and area) was significantly affected by treatment (P < 0.012), with larger values in the AO‐GHD group than in the GHD group (P < 0.05). Factor 5 (weighted primarily by articular cartilage structure and loss of toluidine blue staining scores) also was significantly affected by treatment (P < 0.001), and was significantly lower (less severe lesions) in the GH replete group than in all other treatment groups (P < 0.05). Despite the presence of cartilage lesions, osteophytes and subchondral sclerosis were not observed in GH/IGF‐1–deficient animals.

Conclusion

These results indicate that chronic GH/IGF‐1 deficiency causes an increased severity of articular cartilage lesions of OA without the bony lesions normally seen in this disease.

     

Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritic human articular knee cartilage: A study of proliferation,programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage

Objective

Chondrocytes are crucial for adequate matrix balance and function. Cell proliferation and, recently, extensive apoptotic cell death have been reported in osteoarthritic (OA) cartilage. Apoptotic cell death would be an obvious central factor in the initiation and progression of OA, since there is no potential for replacing articular chondrocytes in the adult. Therefore, we studied the occurrence of apoptotic cell disintegration and cell proliferation in OA and normal articular cartilage obtained from the knees of adult donors of all ages.

Methods

Following immunostaining for cellular proteins as well as staining for nuclear DNA, we performed triple‐channel confocal laser scanning microscopy on thick cartilage slices to evaluate lacunar emptying and cell viability. Cell proliferation and apoptotic cell death were evaluated morphologically, by immunodetection of the proliferation‐associated Ki‐67 antigen, and by the TUNEL reaction.

Results

With the exception of the calcified layer, we were not able to detect any major (apoptotic or nonapoptotic) cell disintegration in normal young or aged articular knee cartilage. Single apoptotic cells were detected in OA articular knee cartilage. A significant increase in lacunar emptying was observed in late‐stage specimens with higher Mankin scores compared with age‐matched normal control cartilage specimens, but not in low‐grade lesions. A significant (but lesser) increase in empty lacunae was also observed with age in normal cartilage. Cell proliferation was rarely detected in OA cartilage samples and was not detected at all in normal cartilage samples.

Conclusion

Our results confirm the findings of previous studies showing that cell proliferation occurs in OA cartilage. They also show that, contrary to previous suggestions, apoptotic cell death is not a widespread phenomenon in aging or OA cartilage.

     

Cathepsin B in osteoarthritis: zonal variation of enzyme activity in human femoral head cartilage.

OBJECTIVES--To determine the quantitative topographical distribution of cathepsin B in human femoral head cartilage by measuring the zonal variation of enzyme activity in specimens taken from various anatomical regions of normal and osteoarthritic (OA) tissues, and to correlate this parameter with the severity of the OA lesions. METHODS--OA articular cartilage was obtained at surgery for total hip replacement and control cartilage obtained at postmortem. Cylinders of full thickness cartilage with underlying bone were retrieved with a biopsy trephine. Sections of cartilage were produced by cryocutting the tissue as slices parallel to the articular surface and assayed for cathepsin B with a specific, highly sensitive fluorogenic substrate. The severity of the OA lesions was graded according to the histopathological-histochemical method of Mankin. RESULTS--Zonal cathepsin B activity of normal cartilage was uniform and low in all regions of the femoral head. In apparently intact OA cartilage and in severely degraded tissue the zonal distribution and the amounts of enzyme were similar to control values. At sites with active disease, cathepsin B activity was much greater than in controls and its irregular zonal distribution correlated with tissue degeneration, hypercellularity, or cloning of chondrocytes as determined histochemically. Particularly high enzyme levels were observed at sites with regenerating cartilage, where some zonal peaks attained 20-fold activity with respect to controls. CONCLUSION--Cathepsin B may play a role in sustaining the chronicity of OA, not as an initiator, but rather as a perpetuator of the disease and as an antagonist of regeneration.     

Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage.

OBJECTIVE: Chondrocytes are crucial for adequate matrix balance and function. Cell proliferation and, recently, extensive apoptotic cell death have been reported in osteoarthritic (OA) cartilage. Apoptotic cell death would be an obvious central factor in the initiation and progression of OA, since there is no potential for replacing articular chondrocytes in the adult. Therefore, we studied the occurrence of apoptotic cell disintegration and cell proliferation in OA and normal articular cartilage obtained from the knees of adult donors of all ages. METHODS: Following immunostaining for cellular proteins as well as staining for nuclear DNA, we performed triple-channel confocal laser scanning microscopy on thick cartilage slices to evaluate lacunar emptying and cell viability. Cell proliferation and apoptotic cell death were evaluated morphologically, by immunodetection of the proliferation-associated Ki-67 antigen, and by the TUNEL reaction. RESULTS: With the exception of the calcified layer, we were not able to detect any major (apoptotic or nonapoptotic) cell disintegration in normal young or aged articular knee cartilage. Single apoptotic cells were detected in OA articular knee cartilage. A significant increase in lacunar emptying was observed in late-stage specimens with higher Mankin scores compared with age-matched normal control cartilage specimens, but not in low-grade lesions. A significant (but lesser) increase in empty lacunae was also observed with age in normal cartilage. Cell proliferation was rarely detected in OA cartilage samples and was not detected at all in normal cartilage samples. CONCLUSION: Our results confirm the findings of previous studies showing that cell proliferation occurs in OA cartilage. They also show that, contrary to previous suggestions, apoptotic cell death is not a widespread phenomenon in aging or OA cartilage.     

Characterization of human synovial fluid cells of 26 patients with osteoarthritis knee for cartilage repair therapy

Aim: To investigate the possibility of chondrogenic differentiation and cartilage repair of synovial fluid cells of osteoarthritis (OA) knee. Methods: Synovial fluids from 26 patients with OA knee were aspirated from each knee joint and cultured in vitro. The morphology of cultured synovial fluid cells, cell proliferation rate, the phenotype, and chondrogenic differentiation were analyzed in in vitro. Also, human autologous synovial fluid cells were transplanted to OA cartilage, and the cells were traced in ex vivo. Results: In 19 of 26 materials, the cells proliferated satisfactorily. The cell proliferation in six materials was very slow and one material contaminated. Culture‐expanded synovial fluid cells had a fibroblastic morphology and the phenotype was negative for CD10, CD14, and CD45, and positive for CD13, CD44, and CD105. Pellet culture of synovial fluid cells showed chondrogenic differentiation. In the ex vivo study, autologous transplanted synovial fluid cells were observed in repaired or enhanced regenerative cartilage areas and showed a tendency to infiltrate the original degenerative cartilage of OA. Conclusions: This study proved the possibility of chondrogenic differentiation of synovial fluid cells of OA knee joints despite the pathologic environment within a diseased joint. Synovial fluid cells were actually heterogeneous cells but they showed chondrogenic differentiation, similar to that of bone marrow‐derived mesenchymal progenitor cells (BMMPCs). The Ex vivo study suggested that synovial fluid cells had a tendency to adhere to OA degenerative cartilage in humans.     

Effects of Spa therapy on serum leptin and adiponectin levels in patients with knee osteoarthritis

Adipocytokine, including leptin and adiponectin, may play an important role in the pathophysiology of osteoarthritis (OA). Spa therapy is one of the most commonly used non-pharmacological approaches for OA, but its mechanisms of action are not completely known. The aim of the present study was to assess whether spa therapy modified plasma levels of leptin and adiponectin in thirty patients with knee OA treated with a cycle of a combination of daily locally applied mud-packs and bicarbonate–sulphate mineral bath water. Leptin and adiponectin plasma levels were assessed at baseline and after 2 weeks, upon completion of the spa treatment period. The concentrations of leptin and adiponectin were measured by ELISA. At basal time, plasma leptin levels were significantly correlated with body mass index (BMI) and gender, but no significant correlation was found with patient age, duration of disease, radiographic severity of knee OA, VAS score or Lequesne index. There was no correlation between plasma adiponectin level and BMI, gender and age, duration of the disease, radiographic severity of knee OA and VAS score. A significant correlation of plasma adiponectin levels was found only with the Lequesne index. At the end of the mud-bath therapy cycle, serum leptin levels showed a slight but not significant increase, while a significant decrease (P < 0.05) in serum adiponectin levels was found. However, leptin and adiponectin concentrations after treatment were not correlated with other clinical parameters. In conclusion, our data show that spa therapy can modify plasma levels of the adipocytokines leptin and adiponectin, important mediators of cartilage metabolism. Whether this effect may play a potential role in OA needs further investigations.