Ano5 deficiency disturbed bone formation by inducing osteoclast apoptosis in Gnathodiaphyseal dysplasia

Abstract

Gnathodiaphyseal dysplasia (GDD) is a rare genetic syndrome characterized by cemento-ossifying fibroma lesions in the mandible and sclerosis of tubular bones. Currently, the clinical treatment of GDD is limited to surgical resection; therefore, novel treatment strategies developed through exploration of the related mechanisms are needed. Mutations in the TMEM16E/ANO5 gene are considered the main pathogenic factor of GDD, and the Ano5 knockout mouse model (Ano5^−/−) established previously, which presented GDD-like characteristics, exhibited decreased osteoclastogenesis. ANO5, a calcium-activated chloride channel (CaCC), plays an important role in the maintenance of intracellular calcium homeostasis, which is crucial for osteoclast differentiation. In this study, our data indicated that the intracellular calcium concentration ([Ca²⁺]_i) and calcium transients were significantly decreased in Ano5^−/− osteoclasts accompanied by abnormally altered expression of calcium transporters, resulting in calcium dyshomeostasis. In addition, the endoplasmic reticulum stress (ERS) response was significantly enhanced in Ano5^−/− osteoclasts, possibly because of calcium dyshomeostasis, which leading to the increased proportion of apoptotic osteoclasts via the activation of the C/EBP homologous protein (CHOP) signalling pathway, accompanied by abnormal changes in the expression of apoptosis-related factors. In summary, Ano5 deficiency impairs the function of osteoclasts by increasing osteoclast apoptosis, which is induced by an overactivated ERS response via calcium dyshomeostasis.