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

Abstract

Objectives-To investigate the role of matrix metalloproteinase (MMP)-13/collagenase-3 in osteoarthritis (OA).Methods-Surgically-induced OA in knees of MMP-13 knock out (KO) and wild type (WT) mice was compared. Femoral and tibial cartilage aggrecan loss (0-3), erosion (0-7) and chondrocyte hypertrophy (0-1), as well as osteophyte size (0-3) and maturity (0-3) were histologically scored. Serial sections were stained for collagen type X and the MMP-generated aggrecan neo-epitope DIPEN.Results-Following surgery, aggrecan loss and cartilage erosion were more severe in the tibia than femur (p<0.01) and tibial cartilage erosion increased with time (p<0.05) in WT mice. Cartilaginous osteophytes were present at 4 weeks and underwent ossification, with size and maturity increasing by 8 weeks (p<0.01). There was no difference between genotypes in aggrecan loss or cartilage erosion at 4 weeks. Tibial cartilage erosion in KO mice was less than WT at 8 weeks (p<0.02). Cartilaginous osteophytes were larger in KO at 4 weeks (p<0.01), but by 8 weeks osteophyte maturity and size were no different from WT. Articular chondrocyte hypertrophy with positive type X collagen and DIPEN staining occurred in both WT and KO joints.Conclusions-These studies have confirmed that structural cartilage damage in mouse experimental OA is dependent on MMP-13 activity. Chondrocyte hypertrophy is not regulated by MMP-13 activity in this model and does not in itself lead to cartilage erosion. MMP-13 deficiency can inhibit cartilage erosion in the presence of aggrecan depletion, supporting the potential for therapeutic intervention in established OA with MMP-13 inhibitors.Progressive erosion of articular cartilage is a significant determinant of prognosis and the need for joint replacement surgery in osteoarthritis (OA). Proteolysis of the principal NIH Public Access Author ManuscriptArthritis Rheum. Author manuscript; available in PMC 2010 December 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cartilage extracellular matrix constituents, aggrecan and the type II/IX/XI collagen network, directly causes erosion as well as predisposing the tissue to mechanical disruption even with loading at physiological levels. Aggrecan proteolysis and loss precedes and may be prerequisite for subsequent collagenolysis (1). A distintegrin and metalloproteinase with thrombospondin repeat (ADAMTS) enzymes are responsible for pathological aggrecanolysis (2,3). ADAMTS-5 is the predominant arthritis-associated enzyme in mice, since animals deficient in ADAMTS-5 activity are protected from cartilage erosion in OA and inflammatory arthritis (4-6). Ablating the ADAMTS cleavage site in the interglobular domain of aggrecan also blocks cartilage structural damage, confirming that the effect in ADAMTS-5-deficient mice is due to inhibition of aggrecanolysis (7).The above studies demonstrate that inhibiting the initiation of aggrecan loss can prevent subsequent structural cartilage damage/erosion in arthritis. Clinically, it is likely that e...

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E2– and cAMP‐dependent pathways in osteoarthritic chondrocytes

“…The fact that XCT790, under both basal and IL-1␤-induced conditions, decreases the expression of MMP-13, a metalloproteinase involved in cartilage destruction (41,42), further supports the view that ERR␣ plays a role in a cartilage-degradation pathway in OA. To our knowledge, this is the first report of a metalloproteinase gene as an ERR␣ target gene.…”

Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

“…Therefore, these results suggest that Dkk-1 inhibits OA cartilage destruction by inhibiting Wnt-induced expression of catabolic factors, such as Mmp13, which play a crucial role in OA cartilage destruction (29).…”

“…The Safranin O-stained slides were further analyzed for osteophyte formation, synovitis, and subchondral bone sclerosis. Osteophyte maturity was scored by examining anteromedial tibia regions in each animal (29). Synovitis was examined by Safranin O and hematoxylin staining of synovium (21).…”

“…Wnt-3a caused up-regulation of Mmp13 and Adamts4 (Figures 6B-D), which encode proteins known to play a role in OA cartilage destruction (29,33). The expression of other catabolic factors examined was not modulated by Wnt-3a treatment (Figures 6B-D).…”

“…In the current study, we used Wnt-3a to evaluate the function of Dkk-1 in chondrocytes, although we did not identify which Wnt molecules were specifically up-regulated in OA cartilage in our experimental system. Wnt-3a activates the canonical Wnt pathway and stimulates the (29). Although ADAMTS-4 appears to be associated with OA pathogenesis (33), Adamts4-knockout mice do not appear to have protection against OA cartilage destruction (41).…”