The Role of Sorting Nexin 10 (Snx10) in Control of Osteoclast Function and Regulation of Bone Homeostasis

Abstract

Sorting Nexin 10 (Snx10) is expressed in osteoclasts and is required for osteoclastic bone resorption in vitro. To study the role of Snx10 in osteoclastic bone resorption and bone homeostasis in vivo, we investigated the expression of Snx10 and created mouse models in which Snx10 was deficient in osteoclasts or globally. Osteoclast-specific Snx10-deficient mice exhibited severe osteopetrosis with abnormal bone micro-architectural parameters in vivo, consistent with the failure of osteoclasts to normally resorb bone. Osteoclast-derived Snx10 deficiency didn’t completely inhibit osteoclast formation, however, the capacity to resorb bone was significantly reduced. Intracellular vesicular transport, ruffled border formation and extracellular acidification were found to be severely impaired due to osteoclast-derived Snx10 deficiency. We also discovered that Snx10 was highly expressed in gastric zymogenic cells, with mutations leading to gastric dysfunction and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to gastric dysfunction and low calcium availability, resulting in impaired bone mineralization and hypocalcemia). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, was thought to occur due to failure of the osteoclasts to maintain normal calcium homeostasis. However, osteoclast-specific Snx10 deficiency had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate prevented the rachitic phenotype and rescued the early death in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human ARO with hypocalcaemia and/or no improvement after HSCT. We concluded that tissue-specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes-fatal consequences. To our knowledge, this is the first study to explore the role of Snx10 using the genetically modified mouse model. This study not only uncovered the cellular mechanism by which Snx10 regulates osteoclastic bone resorption but also established an essential role for Snx10 in bone homeostasis and underscore the importance of Snx10-dependent gastric function in calcium homeostasis.