Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage.

In osteoarthritis (OA) chondrocytes surrounding lesions express elevated bone morphogenetic protein 2 (BMP2) levels. To investigate the functional consequence of chondrocyte-specific BMP2 expression, we made a collagen type II dependent, doxycycline (dox)-inducible BMP2 transgenic mouse and studied the effect of elevated BMP2 expression on healthy joints and joints with experimental OA. We cloned a lentivirus with BMP2 controlled by a tet-responsive element and transfected embryos of mice containing a collagen type II driven cre-recombinase and floxed rtTA to gain a mouse expressing BMP2 solely in chondrocytes and only upon dox exposure (Col2-rtTA-TRE-BMP2). Mice were treated with dox to induce elevated BMP2 expression. In addition, experimental OA was induced (destabilisation of the medial meniscus model) with or without dox supplementation and knee joints were isolated for histology. Dox treatment resulted in chondrocyte-specific upregulation of BMP2 and severely aggravated formation of osteophytes in experimental OA but not in control mice. Moreover, elevated BMP2 levels did not result in alterations in articular cartilage of young healthy mice, although BMP2-exposure did increase VDIPEN expression in the articular cartilage. Strikingly, despite apparent changes in knee joint morphology due to formation of large osteophytes there were no detectible differences in articular cartilage: none with regard to structural damage nor in Safranin O staining intensity when comparing destabilisation of the medial meniscus with or without dox exposure. Our data show that chondrocyte-specific elevation of BMP2 levels does not alter the course of cartilage damage in an OA model in young mice but results in severe aggravation of osteophyte formation.

Blaney Davidson EN ，Vitters EL ，Bennink MB ，van Lent PL ，van Caam AP ，Blom AB ，van den Berg WB ，van de Loo FA ，van der Kraan PM ... -  《-》

Role of Lipocalin-Type Prostaglandin D Synthase in Experimental Osteoarthritis.

Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the formation of prostaglandin D2 (PGD2 ), which has important roles in inflammation and cartilage metabolism. We undertook this study to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse model. Experimental OA was induced in wild-type (WT) and L-PGDS-deficient (L-PGDS-/- ) mice (n = 10 per genotype) by destabilization of the medial meniscus (DMM). Cartilage degradation was evaluated by histology. The expression of matrix metalloproteinase 13 (MMP-13) and ADAMTS-5 was assessed by immunohistochemistry. Bone changes were determined by micro-computed tomography. Cartilage explants from L-PGDS-/- and WT mice (n = 6 per genotype) were treated with interleukin-1α (IL-1α) ex vivo in order to evaluate proteoglycan degradation. Moreover, the effect of intraarticular injection of a recombinant adeno-associated virus type 2/5 (rAAV2/5) encoding L-PGDS on OA progression was evaluated in WT mice (n = 9 per group). Compared to WT mice, L-PGDS-/- mice had exacerbated cartilage degradation and enhanced expression of MMP-13 and ADAMTS-5 (P < 0.05). Furthermore, L-PGDS-/- mice displayed increased synovitis and subchondral bone changes (P < 0.05). Cartilage explants from L-PGDS-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoding L-PGDS attenuated the severity of DMM-induced OA-like changes in WT mice (P < 0.05). The L-PGDS level was increased in OA tissues of WT mice (P < 0.05). Collectively, these findings suggest a protective role of L-PGDS in OA, and therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy.

Najar M ，Ouhaddi Y ，Paré F ，Lussier B ，Urade Y ，Kapoor M ，Pelletier JP ，Martel-Pelletier J ，Benderdour M ，Fahmi H ... -  《-》

Chaperonin 60 regulation of SOX9 ubiquitination mitigates the development of knee osteoarthritis.

Ko JY ，Sun YC ，Li WC ，Wang FS ... -  《-》

Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development.

Little CB ，Barai A ，Burkhardt D ，Smith SM ，Fosang AJ ，Werb Z ，Shah M ，Thompson EW ... -  《-》

Differential patterns of pathology in and interaction between joint tissues in long-term osteoarthritis with different initiating causes: phenotype matters.

To determine if osteoarthritis (OA) progression and joint tissue-pathology associations link specific animal models to different human OA phenotypes. Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA). Joint tissue histopathology was scored day-3 to week-16. Tissue-pathology associations (corrected for time and at week-16) were determined by partial correlation coefficients, and odds ratios (OR) calculated for likelihood of cartilage damage and joint inflammation by ordinal-logistic-regression. Despite distinct temporal patterns of progression, by week-16 joint-wide OA pathology in DMM and AIA was equivalent. Significant pathology associations common to both models included: osteophyte size and maturity (r > 0.4); subchondral bone (SCB) sclerosis and osteophyte maturity (r > 0.25); cartilage erosion and chondrocyte hypertrophy/apoptosis (r > 0.4), SCB sclerosis (r > 0.26), osteophyte size (r > 0.3), and maturity (r > 0.32). DMM-specific associations were between cartilage proteoglycan loss and structural damage (r = 0.56), osteophyte maturity (r = 0.49), size (r = 0.45), and SCB sclerosis (r = 0.28). AIA-specific associations were between SCB sclerosis and chondrocyte hypertrophy/apoptosis (r = 0.40) and osteophyte size (r = 0.37); and synovitis with cartilage structural damage (r = 0.18). No tissue-pathology associations were common to both models at week-16. Increased likelihood of cartilage structural damage was associated with: chondrocyte hypertrophy/apoptosis (OR>1.7), and osteophyte size (OR>2.3) in both models; SCB sclerosis (OR = 2.0) and proteoglycan loss (OR = 2.4) in DMM; and synovitis (OR = 1.2) in AIA. Joint inflammation was associated positively with cartilage proteoglycan loss (OR = 1.4) and inversely with osteophyte size (OR = 0.21) in AIA only. This study highlights the importance of defining OA-models by initiating mechanisms and progression, not just end-stage joint-tissue pathology.

Zaki S ，Smith MM ，Smith SM ，Little CB ... -  《-》