Metalloproteases as potential therapeutic targets in arthritis treatment

Rowan, Andrew D.; Litherland, Gary J.; Wang, Hui; Milner, Jennifer M

doi:10.1517/14728222.12.1.1

Cited by 69 publications

(45 citation statements)

References 147 publications

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“…Compound 60 attracted their attention since it did not contain an obvious Zn-chelating group and showed selectivity over MMP-14-the one isoform postulated to play a role in MSS [112]. With the aid of protein co-crystal structural information, they observed that compound 60 didnot fill the S1 pocket.…”

Section: Non-zinc-chelating-based Mmp-13 Inhibitorsmentioning

confidence: 99%

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

Shi²,

Tang³

et al. 2011

CMC

112

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Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.

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Section: Non-zinc-chelating-based Mmp-13 Inhibitorsmentioning

confidence: 99%

New Hope for the Treatment of Osteoarthritis Through Selective Inhibition of MMP-13

Shi²,

Tang³

et al. 2011

CMC

112

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“…[29][30][31][32][33][34][35][36] In one study, ADAMTS-7 was found to be significantly upregulated in arthritic cartilage and synovium compared with normal controls. 37 Quantitative real-time polymerase chain reaction (PCR) has revealed that while ADAMTS-7 and -12 are both significantly upregulated in RA cartilage, only ADAMTS-12 is significantly upregulated in OA cartilage (unpublished data).…”

Section: Role In Arthritismentioning

confidence: 99%

The emerging roles of ADAMTS-7 and ADAMTS-12 matrix metalloproteinases

Lin¹,

Liu

2009

OARRR

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Abstract:The a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) comprise a family of secreted zinc metalloproteinases with a precisely ordered modular organization. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their dysregulation has been implicated in disease-related processes such as arthritis, atherosclerosis, cancer, and inflammation. ADAMTS-7 and ADAMTS-12 share a similar domain organization to each other and form a subgroup within the ADAMTS family. Emerging evidence suggests that ADAMTS-7 and ADAMTS-12 may play an important role in the development and pathogenesis of various kinds of diseases. In this review, we summarize what is currently known about the roles of these two metalloproteinases, with a special focus on their involvement in chondrogenesis, endochondral ossification, and the pathogenesis of arthritis, atherosclerosis, and cancer. The future study of ADAMTS-7 and ADAMTS-12, as well as the molecules with which they interact, will help us to better understand a variety of human diseases from both a biological and therapeutic standpoint.

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“…Although different etiologies perpetuate these diseases, inflammation (to a greater extent in RA and a lesser extent in OA) contributes to this proteolysis, which is widely believed to be metalloproteinase mediated. The matrix metalloproteinases (MMPs) have received most attention, not least as potential therapeutic targets (1). Indeed, among Ն569 proteinases in the human degradome, ϳ34% are metalloproteinases, but to date no MMP inhibition-based therapeutic approach has demonstrated suitable clinical efficacy (1).…”

Section: Introductionmentioning

confidence: 99%

“…The matrix metalloproteinases (MMPs) have received most attention, not least as potential therapeutic targets (1). Indeed, among Ն569 proteinases in the human degradome, ϳ34% are metalloproteinases, but to date no MMP inhibition-based therapeutic approach has demonstrated suitable clinical efficacy (1). This failure has been attributed to a lack of selectivity of MMP inhibitors as a consequence of the high degree of similarity between MMPs.…”

Section: Introductionmentioning

confidence: 99%