Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice

Abstract

IntroductionDegenerative joint diseases including osteoarthritis (OA) are common, particularly in the elderly. Early signs of OA include progressive loss from articular cartilage of the proteoglycan aggrecan, reflected by a loss of safranin O staining, excessive damage to type II collagen, and general degeneration and fibrillation of the cartilage surface, resulting ultimately in a loss of articular cartilage (1).One of the primary targets of this disease is type II collagen, the major structural collagen found in articular cartilage in healthy individuals. There is ordinarily a strict balance between the production of type II collagen and degradation of this protein by catabolic enzymes during normal remodeling of cartilage (1). Pathological conditions such as OA are characterized by a loss of this balance with increased proteolysis (1-5) and upregulation of the synthesis of type II procollagen (5) and aggrecan (6).Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent enzymes that degrade extracellular matrix components. MMPs are synthesized in articulating joints by synovial cells and chondrocytes. In mature articular cartilage, chondrocytes maintain the cartilage-specific matrix phenotype. Elevated expression of MMPs is associated with cartilage degradation (1). MMP-13, also known as human collagenase-3, is thought to play an important role in type II collagen degradation in articular cartilage and especially in OA (4, 7-9). Type II collagen is the preferred substrate for MMP-13 (4, 7, 10). Expression and contents of MMP-1 (collagenase-1) and 11,12), expression of MMP-8 (collagenase-2), and collagenase activity (4,8) are upregulated in human OA cartilage.Spontaneous development of focal sites degeneration has been described in aging guinea pigs (13). Sublines of the inbred STR/ORT strain of mice also develop spontaneous OA with aging (14). Mice exhibit upregulated expression of MMP-13 and collagenase activity is upregulated in focal lesions (15). In guinea pigs, MMP-1 and MMP-13 are also upregulated in OA lesions associated with increased collagenase activity (16). It has been suggested that increased collagenase-3 (MMP-13) activity plays a pivotal role in the pathogenesis of osteoarthritis (OA). We have used tetracycline-regulated transcription in conjunction with a cartilage-specific promoter to target a constitutively active human MMP-13 to the hyaline cartilages and joints of transgenic mice. Postnatal expression of this transgene resulted in pathological changes in articular cartilage of the mouse joints similar to those observed in human OA. These included characteristic erosion of the articular cartilage associated with loss of proteoglycan and excessive cleavage of type II collagen by collagenase, as well as synovial hyperplasia. These results demonstrate that excessive MMP-13 activity can result in articular cartilage degradation and joint pathology of the kind observed in OA, suggesting that excessive activity of this proteinase can lead to this disease.

Selective inhibition of ADAMTS‐1, ‐4 and ‐5 by catechin gallate esters

“…Our finding that two collagenases implicated in cartilage collagen hydrolysis, collagenase-1 and collagenase-3 [51][52][53][54] were not potently inhibited by EGCG and ECG, is evidence that this is not via direct inhibition of these collagen-degrading enzymes. Other mechanisms are possible, including effects on proinflammatory signalling pathways.…”

Caesalpinia sappan extract inhibits IL1β-mediated overexpression of matrix metalloproteinases in human chondrocytes

“…*indicates significant differences with respect to cells co-transfected with the MMP-13 promoter and the p65/p50 expression vectors (P \ 0.05) MMP-13, in articular chondrocytes are known to promote the cleavage of collagen triple helices allowing further degradation by other MMPs (Nagase and Woessner 1999). Supporting the role of MMP-13 in connective tissue degradation, Neuhold et al (2001) reported that transgenic mice overexpressing MMP-13 show signs of articular cartilage degradation and exhibit joint pathology similar to that found in OA. Our results confirm that IL1b represents a potent inflammatory stimulus that leads to overexpression of MMP-1, MMP-3, and MMP-13 mRNA in primary and SW1353 chondrocytes.…”

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

“…Therefore, our strategy for development of DMOADs was to focus on identification of highly selective allosteric MMP-13 inhibitors free of hydroxamic acid or other zinc-chelating functional groups that contribute to inhibition of multiple MMPs. The rationale for targeting MMP-13 came from 1) overwhelming data on a potential role of MMP-13 in the pathogenesis of OA (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), and 2) data from studies of MMP-13 knockout mice and humans with an MMP-13 mutation, suggesting lack of MSS liability (29)(30)(31)(32).…”

“…It cleaves the triple-helical collagen at a unique site, resulting in a three-quarter-length and a one-quarter-length product (11,12,18). Data on MMP-13-transgenic animals indicate that MMP-13 induces joint abnormalities characteristic of human OA (19). Moreover, semiselective MMP-13 inhibitors block degradation of human OA cartilage cultures (20).…”