OBJECTIVE To investigate the validity of joint space width (JSW) measurements in millimeters (mm) in hand osteoarthritis (OA) patients by comparison to controls, grading of joint space narrowing ... Show moreOBJECTIVE To investigate the validity of joint space width (JSW) measurements in millimeters (mm) in hand osteoarthritis (OA) patients by comparison to controls, grading of joint space narrowing (JSN), and clinical features. METHODS Hand radiographs of 235 hand OA patients (mean age 65 years, 83% women) and 471 controls were used. JSW was measured with semi-automated image analysis software in the distal, proximal interphalangeal and metacarpal joints (DIPJs, PIPJs and MCPJs). JSN (grade 0-3) was assessed using the osteoarthritis research society international (OARSI) atlas. Associations between the two methods and clinical determinants (presence of pain, nodes and/or erosions, decreased mobility) were assessed using Generalized Estimating Equations with adjustments for age, sex, body mass index (BMI) and mean width of proximal phalanx. RESULTS JSW was measured in 5631 joints with a mean JSW of 0.98 mm (standard deviation (SD) 0.21), being the smallest for DIPJs (0.70 (SD 0.25)) and largest for MCPJs (1.40 (SD 0.25)). The JSN=0 group had a mean JSW of 1.28 mm (SD 0.34), the JSN=3 group 0.17 mm (SD 0.23). Controls had larger JSW than hand OA patients (P-value<0.001). In hand OA, females had smaller JSW than men (β -0.08, (95% confidence interval (95% CI) -0.15 to -0.01)) and lower JSW was associated with the presence of pain, nodes, erosions and decreased mobility (adjusted β -0.21 (95% CI -0.27, -0.16), -0.37 (-0.40, -0.34), -0.61 (-0.68, -0.54) and -0.46 (-0.68, -0.24) respectively). These associations were similar for JSN in grades. CONCLUSION In hand OA the quantitative JSW measurement is a valid method to measure joint space and shows a good relation with clinical features. Show less
Objective To study the association between metacarpal bone mineral density (BMD) loss and progressive hand osteoarthritis (OA) over 2 years. Methods Using the Kellgren-Lawrence (KL) grading scale... Show moreObjective To study the association between metacarpal bone mineral density (BMD) loss and progressive hand osteoarthritis (OA) over 2 years. Methods Using the Kellgren-Lawrence (KL) grading scale and the Osteoarthritis Research Society International Atlas, standardised hand radiographs of 181 patients with primary OA at multiple sites (mean age 60 years, 80% women, mean body mass index 27 kg/m(2)) were assessed for hand OA at baseline (KL >= 2 in two or more hand joints) and progressive hand OA over 2 years (>= 1 point increase in total osteophyte and joint space narrowing score in patients with hand OA at baseline). Changes in BMD were measured over 2 years in metacarpals 2-4 by digital x-ray radiogrammetry. Accelerated BMD loss was defined as loss of >3 mg/cm(2)/year. Logistic regression analyses were performed to assess the associations between BMD loss and progressive hand OA. Results The baseline prevalence of hand OA was 68% and, after 2 years, 32% of these patients had progressive hand OA. Accelerated BMD loss was present in 79% of the patients with progressive hand OA compared with 60% and 57% of the patients with non-progressive hand OA and no hand OA, respectively. BMD loss was independently associated with progressive hand OA compared with non-progressive hand OA with a RR (95% CI) of 2.1 (1.1 to 4.3). Conclusion Accelerated metacarpal BMD loss is associated with progressive hand OA over a period of 2 years; knowledge of common mechanisms may lead to development of therapeutic interventions for hand OA. Show less
Guler-Yuksel, M.; Bijsterbosch, J.; Allaart, C.F.; Meulenbelt, I.; Kroon, H.M.; Watt, I.; ... ; Kloppenburg, M. 2011
OBJECTIVE To study the association between metacarpal bone mineral density (BMD) loss and progressive hand osteoarthritis (OA) over 2 years. METHODS Using the Kellgren-Lawrence (KL) grading scale... Show moreOBJECTIVE To study the association between metacarpal bone mineral density (BMD) loss and progressive hand osteoarthritis (OA) over 2 years. METHODS Using the Kellgren-Lawrence (KL) grading scale and the Osteoarthritis Research Society International Atlas, standardised hand radiographs of 181 patients with primary OA at multiple sites (mean age 60 years, 80% women, mean body mass index 27 kg/m(2)) were assessed for hand OA at baseline (KL ≥ 2 in two or more hand joints) and progressive hand OA over 2 years (≥ 1 point increase in total osteophyte and joint space narrowing score in patients with hand OA at baseline). Changes in BMD were measured over 2 years in metacarpals 2-4 by digital x-ray radiogrammetry. Accelerated BMD loss was defined as loss of >3 mg/cm(2)/year. Logistic regression analyses were performed to assess the associations between BMD loss and progressive hand OA. RESULTS The baseline prevalence of hand OA was 68% and, after 2 years, 32% of these patients had progressive hand OA. Accelerated BMD loss was present in 79% of the patients with progressive hand OA compared with 60% and 57% of the patients with non-progressive hand OA and no hand OA, respectively. BMD loss was independently associated with progressive hand OA compared with non-progressive hand OA with a RR (95% CI) of 2.1 (1.1 to 4.3). CONCLUSION Accelerated metacarpal BMD loss is associated with progressive hand OA over a period of 2 years; knowledge of common mechanisms may lead to development of therapeutic interventions for hand OA. Show less
Meulenbelt, I.; Kraus, V.B.; Sandell, L.J.; Loughlin, J. 2011
On November fourth and fifth 2010 a group of more than 100 international investigators gathered in Atlanta for the second Osteoarthritis (OA) Biomarkers Global Initiative workshop titled "Genetics... Show moreOn November fourth and fifth 2010 a group of more than 100 international investigators gathered in Atlanta for the second Osteoarthritis (OA) Biomarkers Global Initiative workshop titled "Genetics and Genomics: New Targets in OA". The first workshop took place in April 2009 and focused on in vitro (soluble) biomarkers whilst the third and final workshop will take place in 2012 and will focus on imaging biomarkers. The OA Research Society International (OARSI) has organized the workshops. In addition to OARSI, the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the Arthritis Foundation, Amgen, Genzyme, the American Orthopaedic Society for Sports Medicine and Pfizer sponsored the second meeting. It was clear from this meeting that experiments in the genetics, epigenetics and genomics of OA, are yielding valuable insights into the etiology of this heterogeneous disease but that much still needs to be learnt. Combining genetic insights with conventional biomarkers and imaging modalities may provide scientists with the enhanced tools to understand this complex disease. With those tools in hand, clinicians and industry can develop protocols to ultimately improve patient care. Show less
Waarsing, J.H.; Kloppenburg, M.; Slagboom, P.E.; Kroon, H.M.; Houwing-Duistermaat, J.J.; Weinans, H.; Meulenbelt, I. 2011
Objective. The identified osteoarthritis (OA) susceptibility genes are mainly active in skeletal development and could thus affect joint geometry. Because nonoptimal joint geometry is a risk factor... Show moreObjective. The identified osteoarthritis (OA) susceptibility genes are mainly active in skeletal development and could thus affect joint geometry. Because nonoptimal joint geometry is a risk factor for the development of OA, we investigated if and how the path that leads from nonoptimal joint geometry to OA of the hip is influenced by these genes. Methods. The shape of the hips of subjects in the Genetics, Osteoarthritis and Progression Study, consisting of sibling pairs with symptomatic OA at multiple joint locations, was quantified by applying a statistical shape model to radiographs. Shape aspects (modes) were correlated to OA characteristics. We then tested for the association of shape modes with OA susceptibility single-nucleotide polymorphisms (SNPs) of GDF5, FRZB, and DIO2. Results. Four of 23 shape modes (mode 1, mode 17, mode 18, and mode 21) were strongly associated with OA characteristics. We observed a significant interaction between carrier status of DIO2 rs12885300 and hip OA characteristics for mode 1 (P = 0.005). This indicates that this specific aspect of hip shape correlates with OA characteristics only in carriers of the susceptibility allele. Conclusion. Our results suggest that it is more likely that the rs12885300 SNP of DIO2 increases the vulnerability of cartilage to nonoptimal bone shapes rather than directly influencing the formation of these shapes. Show less
Objectives The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN... Show moreObjectives The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. Methods The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent. Results None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. Conclusions Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity. Show less
Objective: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA)... Show moreObjective: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. Methods: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. Results: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P=0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3 x 10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. Conclusion: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Kerkhof, H.J.M.; Doherty, M.; Arden, N.K.; Abramson, S.B.; Attur, M.; Bos, S.D.; ... ; Valdes, A.M. 2011
Objective: To clarify the role of common genetic variation in the Interleukin-1 beta (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of... Show moreObjective: To clarify the role of common genetic variation in the Interleukin-1 beta (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. Methods: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. Results: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P > 0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR) = 0.71 95% CI 0.56-0.91; P = 0.006, I-2 = 74%), and achieved borderline statistical significance in a random-effects model (OR = 0.61 95% CI 0.35-1.06 P=0.08). Conclusion: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
OBJECTIVE In order to gain insight in the pathogenesis of erosive hand osteoarthritis (OA), the evolution of erosions in hand OA and risk factors involved were investigated. METHODS The 6-year... Show moreOBJECTIVE In order to gain insight in the pathogenesis of erosive hand osteoarthritis (OA), the evolution of erosions in hand OA and risk factors involved were investigated. METHODS The 6-year evolution in radiographic Verbruggen-Veys anatomical phase was assessed in interphalangeal joints of 236 patients with hand OA (mean age 59 years, 83% women) from the GARP (for 'Genetics ARthrosis and Progression') sibling pair study. Erosive evolution comprised phase transitions from non-erosive to erosive phases and from active erosions to remodelling. Clustering of erosive evolution within patients was assessed using the χ² test. Familial aggregation was evaluated in sibling pairs by estimating ORs for siblings and probands sharing erosive evolution. Local baseline determinants and the effect of high sensitivity C reactive protein were assessed using generalised estimating equations. RESULTS Erosive evolution took place in 181 of 4120 interphalangeal joints at risk (4.4%), corresponding to 60 patients (25.4% of study sample). Erosive evolution was found more often in multiple interphalangeal joints in one patient than would be expected by chance (χ² 373.0, p < 0.001). The adjusted OR (95% CI) for a sibling having erosive evolution if the proband had erosive evolution was 4.7 (1.4 to 15.8). Systemic inflammation was not associated with erosive activity. Independent local determinants were joint space narrowing (OR (95% CI) 8.9 (4.8 to 16.4)) and self-reported pain (OR (95%CI) 2.3 (1.1 to 4.7)). CONCLUSIONS rosive evolution was clustered within patients and families. Local factors were also involved in the evolution. This increase in insight in the pathogenesis of erosive hand OA will contribute to the development of new treatments. Show less
Objective To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the... Show moreObjective To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the pathophysiological process of growth hormone (GH) and insulin-like growth factor type I (IGF-I)-mediated osteoarthritis. Methods We utilised radiographs of the knee and hip joints of 84 patients with controlled acromegaly for a mean of 14.0 years with 189 patients with primary generalised osteoarthritis. Hips and knees with with doubtful or definite osteoarthritis (Kellgren-Lawrence score of >= 1) were compared in the current study. For a semiquantitative assessment of radiological osteoarthritis (range 0-3) osteophytes and JSN of the medial and lateral tibiofemoral and hip joints were scored according to the Osteoarthritis Research Society International atlas. Logistic regression analysis was performed with adjustment for age, sex, body mass index and intrapatient effect. Results Knee and hip osteoarthritis in patients with cured acromegaly was characterised by more osteophytosis (OR 4.1-9.9), but less JSN (OR 0.3-0.5) in comparison with patients with primary osteoarthritis. Patients with acromegaly and osteoarthritis had significantly less self-reported functional disability than patients with primary osteoarthritis (p < 0.001). Self reported functional disability was associated with JSN rather than with osteophytosis. Conclusion Arthropathy caused by GH oversecretion results in osteophytosis and to a lesser extent in JSN. This observation suggests that the GH-IGF-I system is mainly involved in bone formation resulting in osteophytosis, but may possibly protect against cartilage loss. Show less
Evangelou, E.; Valdes, A.M.; Kerkhof, H.J.M.; Styrkarsdottir, U.; Zhu, Y.Y.; Meulenbelt, I.; ... ; Translation Res Europe Appl 2011
Objectives Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint... Show moreObjectives Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. Methods A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. Results With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p = 9.2 x 10(-9)), thereby confirming its role as a susceptibility locus for OA. Conclusion The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment. Show less
OBJECTIVE To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the... Show moreOBJECTIVE To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the pathophysiological process of growth hormone (GH) and insulin-like growth factor type I (IGF-I)-mediated osteoarthritis. METHODS We utilised radiographs of the knee and hip joints of 84 patients with controlled acromegaly for a mean of 14.0 years with 189 patients with primary generalised osteoarthritis. Hips and knees with with doubtful or definite osteoarthritis (Kellgren-Lawrence score of ≥ 1) were compared in the current study. For a semiquantitative assessment of radiological osteoarthritis (range 0-3) osteophytes and JSN of the medial and lateral tibiofemoral and hip joints were scored according to the Osteoarthritis Research Society International atlas. Logistic regression analysis was performed with adjustment for age, sex, body mass index and intrapatient effect. RESULTS Knee and hip osteoarthritis in patients with cured acromegaly was characterised by more osteophytosis (OR 4.1-9.9), but less JSN (OR 0.3-0.5) in comparison with patients with primary osteoarthritis. Patients with acromegaly and osteoarthritis had significantly less self-reported functional disability than patients with primary osteoarthritis (p < 0.001). Self reported functional disability was associated with JSN rather than with osteophytosis. CONCLUSION Arthropathy caused by GH oversecretion results in osteophytosis and to a lesser extent in JSN. This observation suggests that the GH-IGF-I system is mainly involved in bone formation resulting in osteophytosis, but may possibly protect against cartilage loss. Show less
Objective In order to gain insight in the pathogenesis of erosive hand osteoarthritis (OA), the evolution of erosions in hand OA and risk factors involved were investigated. Methods The 6-year... Show moreObjective In order to gain insight in the pathogenesis of erosive hand osteoarthritis (OA), the evolution of erosions in hand OA and risk factors involved were investigated. Methods The 6-year evolution in radiographic Verbruggen-Veys anatomical phase was assessed in interphalangeal joints of 236 patients with hand OA (mean age 59 years, 83% women) from the GARP (for 'Genetics ARthrosis and Progression') sibling pair study. Erosive evolution comprised phase transitions from non-erosive to erosive phases and from active erosions to remodelling. Clustering of erosive evolution within patients was assessed using the chi(2) test. Familial aggregation was evaluated in sibling pairs by estimating ORs for siblings and probands sharing erosive evolution. Local baseline determinants and the effect of high sensitivity C reactive protein were assessed using generalised estimating equations. Results Erosive evolution took place in 181 of 4120 interphalangeal joints at risk (4.4%), corresponding to 60 patients (25.4% of study sample). Erosive evolution was found more often in multiple interphalangeal joints in one patient than would be expected by chance (chi(2) 373.0, p < 0.001). The adjusted OR (95% CI) for a sibling having erosive evolution if the proband had erosive evolution was 4.7 (1.4 to 15.8). Systemic inflammation was not associated with erosive activity. Independent local determinants were joint space narrowing (OR (95% CI) 8.9 (4.8 to 16.4)) and self-reported pain (OR (95% CI) 2.3 (1.1 to 4.7)). Conclusions Erosive evolution was clustered within patients and families. Local factors were also involved in the evolution. This increase in insight in the pathogenesis of erosive hand OA will contribute to the development of new treatments. Show less
Objective To investigate the long-term clinical and radiographic disease course of hand osteoarthritis (OA) and determinants of outcome. Methods Clinical and radiographic measures were obtained at... Show moreObjective To investigate the long-term clinical and radiographic disease course of hand osteoarthritis (OA) and determinants of outcome. Methods Clinical and radiographic measures were obtained at baseline and after 6 years in 289 patients with hand OA (mean age 59.5 years, 83.0% women). Clinical outcomes were self-reported pain and functional limitations assessed with the Australian/Canadian Osteoarthritis Hand Index (AUSCAN). Poor clinical outcome was defined as a follow-up score not fulfilling the Patient Acceptable Symptom State. Radiographic outcome was assessed by osteophytes and joint space narrowing (JSN) on standardised hand radiographs using the Osteoarthritis Research Society International (OARSI) atlas. Radiographic progression was defined as a change in osteophytes or JSN, above the smallest detectable change. Change in outcome measures was calculated and baseline determinants for poor clinical outcome and radiographic progression were assessed using logistic regression analysis. Results Clinical change showed great variation, with half of the population reporting deterioration. Poor outcome in pain was related to high levels of functional limitations and a high number of painful joints at baseline. Poor outcome on functional limitations was related to high baseline pain levels. Radiographic progression was present in 52.5% of patients and associated with high baseline levels of pain, nodes, osteophytes and the presence of erosive OA and nodal OA. Clinical change and radiographic progression were not related. Conclusions This study gives insight in the clinical and radiographic course of hand OA as well as determinants of outcome. These findings enable better patient information on prognosis. The relationship between clinical and radiographic outcome needs further investigation. Show less
Meulenbelt, I.; Bos, S.D.; Chapman, K.; Breggen, R. van der; Houwing-Duistermaat, J.J.; Kremer, D.; ... ; Slagboom, E. 2011
Objective To study whether common genetic variants of the genes involved in the complex regulatory mechanism determining the intracellular bio-availability of T3 influence osteoarthritis onset.... Show moreObjective To study whether common genetic variants of the genes involved in the complex regulatory mechanism determining the intracellular bio-availability of T3 influence osteoarthritis onset. Methods In total 17 genetic variants within the genes encoding WD40-repeat/SOCS-box protein 1, ubiquitin specific protease 33, thyroid hormone receptor alpha, deiodinase, iodothyronine, type III (DIO3) and Indian hedgehog were measured and associated with osteoarthritis in a meta-analyses in European populations from the UK, The Netherlands, Greece and Spain containing a total of 3252 osteoarthritis cases and 2132 controls. Results The minor allele of the DIO3 variant rs945006 showed suggestive evidence for protective association in the overall meta-analyses, which was supported by individual osteoarthritis studies and osteoarthritis subtypes. The association appeared most significant in cases with knee and/or hip with an allelic OR of 0.81 (95% CI 0.70 to 0.930) with a nominal p value of 0.004 and a permutation-based corrected p value for multiple testing of 0.039. Conclusion The findings suggest that the DIO3 gene modulates osteoarthritis disease risk; however, additional studies are necessary to replicate our findings. To elucidate the molecular mechanisms focus should be on the local adaptation to T3 availability either during the endochondral ossification process or during ageing of the articular cartilage. Show less
