Serpins in cartilage and osteoarthritis: what do we know?

Abstract

Serpins (serine proteinase inhibitors) are an ancient superfamily of structurally similar proteins, the majority of which use an elegant suicide inhibition mechanism to target serine proteinases. Despite likely evolving from a single common ancestor, the 36 human serpins have established roles regulating diverse biological processes, such as blood coagulation, embryonic development and extracellular matrix (ECM) turnover. Genetic mutations in serpin genes underpin a host of monogenic disorders — collectively termed the ‘serpinopathies’ — but serpin dysregulation has also been shown to drive pathological mechanisms in many common diseases. Osteoarthritis is a degenerative joint disorder, characterised by the progressive destruction of articular cartilage. This breakdown of the cartilage is driven by the metalloproteinases, and it has long been established that an imbalance of metalloproteinases to their inhibitors is of critical importance. More recently, a role for serine proteinases in cartilage destruction is emerging; including the activation of latent matrix metalloproteinases and cell-surface receptors, or direct proteolysis of the ECM. Serpins likely regulate these processes, as well as having roles beyond serine proteinase inhibition. Indeed, serpins are routinely observed to be highly modulated in osteoarthritic tissues and fluids by ‘omic analysis, but despite this, they are largely ignored. Confusing nomenclature and an underappreciation for the role of serine proteinases in osteoarthritis (OA) being the likely causes. In this narrative review, serpin structure, biochemistry and nomenclature are introduced, and for the first time, their putative importance in maintaining joint tissues — as well as their dysregulation in OA — are explored.

Matrix metalloproteinase‐13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha‐1 antitrypsin: Implications for osteoarthritis

“…The serpins are a superfamily of structurally similar proteins, the majority of which inhibit serine proteinases, and we have recently described their emerging role in cartilage [61]. In this study, we have identified remarkably high transcript expression levels of SERPINA1 gene in human cartilage.…”

“…Our study both supports and compliments these observations and provides novel insights into the proteolytic interplay between AAT, neutrophil elastase and MMP‐13, with potential consequences for the destruction of OA cartilage. AAT can have a role beyond proteinase inhibition [61] and the authors conclude that AAT was not only chondroprotective but also anti‐inflammatory and has a significant effect on pain [72]. This study and our own highlight the need to also investigate the effects of AAT administration using in vivo models of OA, with direct quantification of cartilage degradation, pain and inflammation.…”

FGF receptor inhibitor BGJ398 partially rescues osteoarthritis-like phenotype in older high molecular weight FGF2 transgenic mice via multiple mechanisms

“…Interestingly, increased Col1a2 expression has previously been reported in osteoarthritic cartilage, in contrast to little or no expression in normal articular cartilage 35 . Serpine1 belongs to a family of serine proteinase inhibitors whose function, beyond inhibiting serine proteinases, is only recently emerging 36 . The role of Serpine1, that encodes for plasminogen activator inhibitor 1(PAI) in OA, is controversial since both increased and decreased expression have been reported in OA 36 .…”

“…Serpine1 belongs to a family of serine proteinase inhibitors whose function, beyond inhibiting serine proteinases, is only recently emerging 36 . The role of Serpine1, that encodes for plasminogen activator inhibitor 1(PAI) in OA, is controversial since both increased and decreased expression have been reported in OA 36 . Some models suggest that osteoarthritic cartilage may lose the ability to produce protease inhibitors and that the subsequent imbalance between proteases and their inhibitors may contribute to chondropathy 37 .…”

A Novel Mutation of the KLK6 Gene in a Family With Knee Osteoarthritis

“…For instance, obesity-induced biomechanical overload on joints results in periarticular trauma and joint deformity constituting the mechanical pathogenesis of KOA. Recent studies ( Wilkinson, 2021 ) have shown that genetic mutations in cartilage matrix proteins can induce the onset of KOA lesions. This suggests that KOA may be a hereditary disease in some cases.…”