Systemic sclerosis skin is a 'primed' microenvironment for soft tissue calcification - a hypothesis

Calcinosis cutis, defined as sub-epidermal deposition of calcium salts, is a major clinical problem in patients with systemic sclerosis (SSc), affecting 20-40% of patients. A number of recognised associates of calcinosis have been identified, including disease duration, digital ischaemia and acro-osteolysis. Yet to date, the pathogenesis of SSc-related calcinosis remains unknown and currently there is no effective disease-modifying pharmacotherapy. Following onset of SSc, there are marked changes in the extracellular matrix (ECM) of the skin, notably a breakdown in the microfibrillar network and accumulation of type I collagen. Our hypothesis is that these pathological changes reflect a changing cellular phenotype and result in a primed microenvironment for soft tissue calcification, with SSc fibroblasts adopting a pro-osteogenic profile and specific 'driving forces' promoting tissue mineralisation. Considering the role of the ECM in disease progression may help elucidate the mechanism(s) behind SSc-related calcinosis and inform the development of future therapeutic interventions.