Skin Chronological Aging Drives Age-Related Bone Loss via Secretion of Cystatin-A

Abstract

Although clinical evidence has indicated an association between skin atrophy and bone loss during ageing, their causal relationship and the underlying mechanisms are unknown. Here we show that premature skin ageing drives age-related bone loss in mice. We further identify that cystatin-A (Csta), a keratinocyte-enriched secreted factor, mediates the effect of skin on bone. Keratinocyte-derived Csta binds the receptor for activated C-kinase 1 (Rack1) in osteoblast and osteoclast progenitors, thus promoting their proliferation, but inhibiting osteoclast differentiation. Csta secretion decreases with skin ageing in mice and humans, thereby causing senile osteoporosis by decreasing osteoblasts and osteoclasts numbers differentially. In contrast, topical application of calcipotriol stimulates Csta production in the epidermis and alleviates osteoporosis. These results uncover a mode of endocrine regulation of bone metabolism in the skin, identify Csta as an epidermally derived hormone linking skin ageing to bone loss, and calcipotriol as a promising topical drug for senile osteoporosis.