Osteoarthritis, genetic and molecular mechanisms

Abstract

Osteoarthritis (OA) is the most common musculoskeletal disorder world-wide and has enormous social and economic consequences. OA is a multifactorial disorder in which ageing, genetic, hormonal and mechanical factors are all major contributors to its onset and progression. The primary lesion in OA would appear to occur in the articular cartilage (AC) which covers the weight-bearing surfaces of diarthrodial joints. Studies on AC have shown a decline in the chondrocyte numbers and their viability with ageing; largely due to nitric oxide radical mediated apoptosis. Since chondrocytes are responsible for the synthesis of the extensive extracellular matrix of AC, their decline in numbers limits the AC's ability to maintain homeostasis and thus functionality. Moreover, the chondrocytes remaining in the AC show diminished capacity to respond to growth factors which also restricts repair and their metabolism is greatly affected by cytokines and nitric oxide free radical produced during synovial inflammation and the imposition of supranormal mechanical stresses. Proteoglycans (PGs) provide the resilience of AC and a reduction in their synthesis, molecular size and increased catabolism in OA joints, marked lyimpairs AC capacity to efficiently respond to mechanical stress, leading to fibrillation and erosion down to subchondral bone. Recent OA research has sought to identify modalities which retard, or even reverse these pathological events. While many claims of disease modifying drugs in OA (DMOAD) have been made, our research has indicated that calcium pentosan polysulfate (CaPPS) exhibits considerable potential in this regard. CaPPS corrects many of the phenotypic imbalances (described above) in chondrocyte metabolism and promotes the synthesis of large PGs. Furthermore, it inhibits the enzymes responsible for PG and collagen degradation and increases the translation of tissue inhibitor of metalloproteinase-3 (TIMP-3) by synoviocytes and chondrocytes, thereby, reducing proteolytic and angiogenic activity within the joint space.