Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics

Abstract

Cartilage destruction is a key characteristic of arthritic disease, a process now widely established to be mediated by metzincins such as MMPs. Despite showing promise in preclinical trials during the 1990s, MMP inhibitors for the blockade of extracellular matrix turnover in the treatment of cancer and arthritis failed clinically, primarily due to poor selectivity for target MMPs. In recent years, roles for serine proteinases in the proteolytic cascades leading to cartilage destruction have become increasingly apparent, renewing interest in the potential for new therapeutic strategies that utilize pharmacological inhibitors against this class of proteinases. Herein, we describe key serine proteinases with likely importance in arthritic disease and highlight recent advances in this field. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

Identification of Proteinase Activated Receptor (PAR) cleaving enzymes in human osteoarthritis knee joint synovial fluids

“…The role of MMPs in particular, as a class of enzymes that digest ECM components and cause cartilage degradation, is well established 56 . More recently it has emerged that other classes of enzymes such as serine proteinases are also upregulated in OA and may participate in proteolytic cascades leading to cartilage destruction 57 . All of the enzymes that are implicated in OA pathology also trigger pro-inflammatory signalling cascades through the activation of the PAR family of GPCRs 10 .…”

Collagenolytic matrix metalloproteinases antagonize proteinase-activated receptor-2 activation, providing insights into extracellular matrix turnover

“…However, it is now clear that proteinases also perform precise and specific functions in both homeostasis and disease. The cleavage of triple helical collagens such as type II collagen (the major structural component present in cartilage) by the soluble collagenase subset of matrix metalloproteinases (MMP-1, MMP-8 and MMP- 13) represents an example of highly specific proteolysis whereby only a single peptide bond is cleavable under normal physiological conditions (3). This initial cleavage then leads to collagen denaturation, concomitant with increased susceptibility to other less specific proteinases and disassembly of the collagen network which is a requirement as cartilage is remodelled into bone during development, but also occurs during cartilage breakdown in degenerative scenarios such as rheumatoid arthritis (RA) and osteoarthritis (OA).…”

“…We have demonstrated that an activator of PAR2, matriptase, induces cartilage destruction in a PAR2-and metalloproteinasedependent manner (10,11) and that a related serine proteinase, hepsin, can also activate PAR2 albeit in a markedly less efficient manner (12). Indeed, in complex disease environments (such as arthritis) multiple proteinases could be present to act on PAR2 making our understanding of how PAR2 is activated and regulated important (reviewed in (13)).…”

Translating the matrix

“…Proteolytic turnover of the ECM in the inflamed joint is the focus of a review from Wilkinson et al . (), which explores the therapeutic approaches being used to target serine proteases in joint diseases. The targeting of other classes of proteases such as the MMPs, ADAMS and ADAMTSs, which play roles in various diseases via the use of monoclonal antibodies as therapeutic inhibitors, is discussed by Santamaria and de Groot ().…”

“…This presents the opportunity to utilize the LAP technology to protect other molecules, such as cytokine or growth factor-based drugs, and for their release to be targeted, for example, in areas where there are high levels of proteases such as the arthritic joint. Proteolytic turnover of the ECM in the inflamed joint is the focus of a review from Wilkinson et al (2019), which explores the therapeutic approaches being used to target serine proteases in joint diseases. The targeting of other classes of proteases such as the MMPs, ADAMS and ADAMTSs, which play roles in various diseases via the use of monoclonal antibodies as therapeutic inhibitors, is discussed by Santamaria and de Groot (2019).…”