Regulation of the Osteocyte Secretome with Aging and Disease.

As the most numerous and long-lived of all bone cells, osteocytes have essential functions in regulating skeletal health. Through the lacunar-canalicular system, secreted proteins from osteocytes can reach cells throughout the bone. Furthermore, the intimate connectivity between the lacunar-canalicular system and the bone vasculature allows for the transport of osteocyte-secreted factors into the circulation to reach the entire body. Local and endocrine osteocyte signaling regulates physiological processes such as bone remodeling, bone mechanoadaptation, and mineral homeostasis. However, these processes are disrupted by impaired osteocyte function induced by aging and disease. Dysfunctional osteocyte signaling is now associated with the pathogenesis of many disorders, including chronic kidney disease, cancer, diabetes mellitus, and periodontitis. In this review, we focus on the targeting of bone and extraskeletal tissues by the osteocyte secretome. In particular, we highlight the secreted osteocyte proteins, which are known to be dysregulated during aging and disease, and their roles during disease progression. We also discuss how therapeutic or genetic targeting of osteocyte-secreted proteins can improve both skeletal and systemic health.