A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis

Transforming growth factor beta (TGFβ) is a growth factor with many faces. In our osteoarthritis (OA) research we have found that TGFβ can be protective as well as deleterious for articular cartilage. We postulate that the dual effects of TGFβ on chondrocytes can be explained by the fact that TGFβ can signal via different receptors and related Smad signaling routes. On chondrocytes, TGFβ not only signals via the canonical type I receptor ALK5 but also via the ALK1 receptor. Notably, signaling via ALK5 (Smad2/3 route) results in markedly different chondrocyte responses than ALK1 signaling (Smad1/5/8), and we postulate that the balance between ALK5 and ALK1 expression on chondrocytes will determine the overall effect of TGFβ on these cells. Importantly, signaling via ALK1, but not ALK5, stimulates MMP-13 expression by chondrocytes. In cartilage of ageing mice and in experimental OA models we have found that the ALK1/ALK5 ratio is significantly increased, favoring TGFβ signaling via the Smad1/5/8 route, changes in chondrocyte differentiation and MMP-13 expression. Moreover, human OA cartilage showed a significant correlation between ALK1 and MMP-13 expression. In this paper we summarize concepts in OA, its link with ageing and disturbed growth factor responses, and a potential role of TGFβ signaling in OA development

Elevated extracellular matrix production and degradation upon bone morphogenetic protein-2 (BMP-2) stimulation point toward a role for BMP-2 in cartilage repair and remodeling

Bone morphogenetic protein-2 (BMP-2) has been proposed as a tool for cartilage repair and as a stimulant of chondrogenesis. In healthy cartilage, BMP-2 is hardly present, whereas it is highly expressed during osteoarthritis. To assess its function in cartilage, BMP-2 was overexpressed in healthy murine knee joints and the effects on proteoglycan (PG) synthesis and degradation were evaluated. Moreover, the contribution of BMP in repairing damage induced by interleukin-1 (IL-1) was investigated. Ad-BMP-2 was injected intra-articularly into murine knee joints, which were isolated 3, 7, and 21 days after injection for histology, immunohistochemistry, and autoradiography. In addition, patellar and tibial cartilage was isolated for RNA isolation or measurement of PG synthesis by means of 35SO4 2- incorporation. To investigate the role for BMP-2 in cartilage repair, cartilage damage was induced by intra-articular injection of IL-1. After 2 days, Ad-BMP-2, Ad-BMP-2 + Ad-gremlin, Ad-gremlin, or a control virus was injected. Whole knee joints were isolated for histology at day 4 or patellae were isolated to measure 35SO42- incorporation. BMP-2 stimulated PG synthesis in patellar cartilage on all days and in tibial cartilage on day 21. Aggrecan mRNA expression had increased on all days in patellar cartilage, with the highest increase on day 7. Collagen type II expression showed a similar expression pattern. In tibial cartilage, collagen type II and aggrecan mRNA expression had increased on days 7 and 21. BMP-2 overexpression also induced increased aggrecan degradation in cartilage. VDIPEN staining (indicating matrix metalloproteinase activity) was elevated on day 3 in tibial cartilage and on days 3 and 7 in patellar cartilage, but no longer was by day 21. Increased NITEGE staining (indicating aggrecanase activity) was found on days 7 and 21. In IL-1-damaged patellar cartilage, BMP-2 boosted PG synthesis. Blocking of BMP activity resulted in a decreased PG synthesis compared with IL-1 alone. This decreased PG synthesis was associated with PG depletion in the cartilage. These data show that BMP-2 boosts matrix turnover in intact and IL-damaged cartilage. Moreover, BMP contributes to the intrinsic repair capacity of damaged cartilage. Increased matrix turnover might be functional in replacing matrix molecules in the repair of a damaged cartilage matrix

Age-dependent alteration of TGF-β signalling in osteoarthritis

Osteoarthritis (OA) is a disease of articular cartilage, with aging as the main risk factor. In OA, changes in chondrocytes lead to the autolytic destruction of cartilage. Transforming growth factor-β has recently been demonstrated to signal not only via activin receptor-like kinase 5 (ALK5)-induced Smad2/3 phosphorylation, but also via ALK1-induced Smad1/5/8 phosphorylation in articular cartilage. In aging cartilage and experimental OA, the ratio ALK1/ALK5 has been found to be increased, and the expression of ALK1 is correlated with matrix metalloproteinase-13 expression. The age-dependent shift towards Smad1/5/8 signalling might trigger the differentiation of articular chondrocytes with an autolytic phenotype

Pain descriptors and determinants of pain sensitivity in knee osteoarthritis: A community-based cross-sectional study

Objectives: The aim was to explore pain characteristics in individuals with knee OA (KOA), to compare pain sensitivity across individuals with KOA, individuals with chronic back pain (CBP) and pain-free individuals (NP) and to examine the relationship between clinical characteristics and pain sensitivity and between pain characteristics and pain sensitivity in KOA. Methods: We carried out a cross-sectional, community-based online survey. Two data sets were combined, consisting of Dutch individuals ≥40 years of age, who were experiencing chronic knee pain (KOA, n = 445), chronic back pain (CBP, n = 504) or no pain (NP, n = 256). Demographic and clinical characteristics, global health, physical activity/exercise and pain characteristics, including intensity, spreading, duration, quality (short-form McGill pain questionnaire) and sensitivity (pain sensitivity questionnaire), were assessed. Differences between (sub)groups were examined using analyses of variance or χ2 tests. Regression analyses were performed to examine determinants of pain sensitivity in the KOA group. Results: The quality of pain was most commonly described as aching, tender and tiring-exhausting. Overall, the KOA group had higher levels of pain sensitivity compared with the NP group, but lower levels than the CBP group. Univariately, pain intensity, its variability and spreading, global health, exercise and having co-morbidities were weakly related to pain sensitivity (standardized β: 0.12-0.27). Symptom duration was not related to pain sensitivity. Older age, higher levels of continuous pain, lower levels of global health, and exercise contributed uniquely, albeit modestly, to pain sensitivity (P < 0.05). Conclusion: Continuous pain, such as aching and tenderness, in combination with decreased physical activity might be indicative for a subgroup of individuals at risk for pain sensitivity and, ultimately, poor treatment outcomes

Effect of bone morphogenetic protein-2 (BMP-2) overexpression on mRNA levels of extracellular matrix molecules and proteoglycan (PG) synthesis

<p><b>Copyright information:</b></p><p>Taken from "Elevated extracellular matrix production and degradation upon bone morphogenetic protein-2 (BMP-2) stimulation point toward a role for BMP-2 in cartilage repair and remodeling"</p><p>http://arthritis-research.com/content/9/5/R102</p><p>Arthritis Research & Therapy 2007;9(5):R102-R102.</p><p>Published online 8 Oct 2007</p><p>PMCID:PMC2212581.</p><p></p> Relative expression of mRNA levels of extracellular matrix molecules. Cartilage of mice injected with either Ad-BMP-2 or Ad-luc was isolated after 3, 7, and 21 days. Cartilage was pooled per group per time point, and RNA was isolated. Cycle threshold values were first corrected for and then for the viral control, after which the fold increase/decrease was calculated. Decreases in mRNA levels compared with controls are on the negative scale. BMP-2 induced elevated levels of collagen type II and aggrecan. No changes in collagen type X expression were found. Effect of BMP-2 overexpression on PG synthesis. Murine knee joints were injected with either Ad-BMP-2 or a control virus. Cartilage was isolated 3, 7, or 21 days after viral injection and incubated with SO, after which the amount of incorporation was measured . To perform autoradiography, mice were injected with SOintraperitoneally prior to knee joint isolation, which was performed 3, 7, or 21 days after viral injection. These data show that BMP-2 stimulation of cartilage results in increased synthesis of PGs. Statistical analysis with a Student test. *< 0.05; **< 0.005; ***< 0.0005. N.D., not detectable