Role of degrading enzymes in pathogenesis of osteoarthritis and its implication in therapy

Abstract

SUMMARY AND CONCLUSION O steoarthritis (OA) is the most common form ofarthritis and a major cause of pain and disability in older adults. OA is often referred to as degenerative jointdisease. This is a misnomer because OA is not simply aprocess of wear and tear, but rather, an abnormalremodeling of joint tissues driven by a host of inflammatorymediators within the affected joint. Despite the multifactorial nature of OA, thepathologic changes seen in osteoarthritic joints havecommon features that affect the entire joint structure, resulting in pain, deformity, and loss of function.The pathologic changes seen in OA joints include degradation of the articularcartilage, thickening of the subchondral bone, formationof osteophytes, variable degrees of inflammation of thesynovium, degeneration of ligaments in addition todegeneration of menisci and hypertrophy of the joint capsulein cases of knee OA. It is believed that proteolytic enzymes are the main agentsresponsible for the degradation of cartilage components in osteoarthritis. Currently two classesof proteases are thought to be the major mediators of collagen and proteoglycan cleavage.Collagen degradation was thought to be majorly due to the action of MMP (matrixmetalloproteinase) collagenases while members of both MMP and ADAMTS (a disintegrinand metalloproteinase with thrombospondin motifs) families are important mediators of thedegradation of proteoglycans which due to their extended core protein conformation aresusceptible to the action of many proteases. However, there is increasing evidence for the role of the cysteine protease cathepsin K in collagendegradation in articular cartilage in addition to matriptase-1 and HtrA-1 that belongs to serine protease family. Studies have identified anetwork of factors and pathways that are involved in pathogenesis of osteoarthritis by regulating MMPs and ADAMTS expression in chondrocytes, for instance hypoxia-inducible factor-2a (HIF-2a) which is highlyenhanced in OA cartilage and drives catabolic metalloproteinases such as MMP-1 and mechanical stimuli which act onchondrocytes by stimulating proteinase expression via RUNX2 andIndian hedgehog. Conversely, protective mechanical stimuli can inhibitproteinase expression through CITED2 and FGF-2.One of the pathways is Wnt signaling pathway which may play a role in cartilagedestruction in OA through promotion of chondrocyte-hypertrophy and stimulating an increase inproteinase expression. Mechanisms regulatingcartilage expression of enzymes such as HtrA1, matriptase andcathepsin K require further study. Similarly, whilst TIMP-3 is known tobe able to protect cartilage by inhibitingMMPs and ADAMTSs, the role ofendogenous serine and cysteine proteinase inhibitors in OA remainspoorly studied. Appreciation of the molecular mechanismsinvolved in the pathophysiology of OA makesit easier to understand why many symptomaticapproaches to the treatment of this diseasehave failed. Current approaches are largely palliative andmodifying the structural progression of OA has become a focusof drug development (DMOADs).Some of the DMOADs investigated in clinical trials are those targeting degrading enzymes inhibition. Selective MMP-13 inhibitor is developed to be free from zinc-chelating functional groups, thus minimising potential causes of musceloskeletal syndrom. Research into MMP inhibitors isongoing. However, Phase III evidence for the clinical use ofMMP inhibitors as DMOADs is lacking.More recently, newMMP-13 inhibitor, that is effective and suitable for intra-articular injection, has been reported. The oraladministration of aggrecanase inhibitor, AGC-523 reduced aggrecan fragment ina rat meniscal tear model, suggested a potential preventive role in progression of OA and the efficacy of AGC-523 has been now being investigated in a clinicaltrial. In preclinical models, cathepsin K inhibition showed beneficialeffects on protection of subchondral bone loss and againstcartilage degradation, and suggested reduced osteophyteformation. No DMOAD has yet been approved. Further research is needed to fully delineate the role of individualproteinasesin joint componentsother than cartilage to understand if proteinase inhibitorsare to be developed as OA therapeutics. The key concept to manage DMOAD development will beto target patients selectively according to the drug propertiesbecause OA, like other pathologies, is a heterogeneous diseaseand not all OA patients will respond to a sole drug. Indeed, for maximal benefit, a next step in DMOAD research is likelyto evaluate a drug in patients in whom specific features as wellas disease stage have been identified.