A comprehensive perspective on the role of vitamin D signaling in maintaining bone homeostasis: Lessons from animal models

Abstract

1,25(OH)₂D₃ is well known for its role in maintaining normal serum calcium levels. Through its receptor, 1,25(OH)₂D₃ enhances intestinal calcium absorption and renal calcium reabsorption, thereby ensuring serum calcium levels are within physiological range, which is in turn important for normal bone development and mineralization. The vitamin D receptor (VDR) achieves this via transcriptional induction of genes important in calcium transport. When intestinal and renal calcium (re)absorption is impaired, VDR-mediated signaling will stimulate bone resorption and inhibit mineralization in order to maintain normal serum calcium levels, as evidenced in mice with a systemic or intestine-specific deletion of the VDR. However, VDR signaling in bone is also reported to have anabolic effects. In this review we will discuss the effects of 1,25(OH)₂D₃-mediated VDR signaling on bone homeostasis and provide an overview of the in vitro experiments and various transgenic mice models that have been generated to unravel the role of VDR signaling in different bone cell types such as chondrocytes, (pre)osteoblasts, osteocytes, and (pre)osteoclasts.