Role of local vitamin D signaling and cellular calcium transport system in bone homeostasis

Mouse genetic studies have demonstrated that the 1,25-dihydroxyvitamin D [1,25(OH)(2)D] endocrine system is required for calcium (Ca2+) and bone homeostasis. These studies reported severe hypocalcemia and impaired bone mineralization associated with rickets in mutant mice. Specific phenotypes of these mice with an engineered deletion of 1,25(OH)(2)D cell signaling resemble the features observed in humans with the same congenital disease or severe 1,25(OH)(2)D deficiency. Decreased active intestinal Ca2+ absorption because of reduced expression of epithelial Ca2+ channels is a crucial mechanism that contributes to the major phenotypes observed in the mutant mice. The importance of intestinal Ca2+ absorption supported by 1,25(OH)(2)D-mediated transport was further emphasized by the observation that Ca2+ supplementation rescues hypocalcemia and restores bone mineralization in both patients and mice lacking 1,25(OH)(2)D signaling. This observation questions the direct role of 1,25(OH)(2)D signaling in bone tissue. Studies regarding tissue-specific manipulation of 1,25(OH)(2)D function have provided a consensus on this issue by demonstrating a direct action of 1,25(OH)(2)D on cells in bone tissue through bone metabolism and mineral homeostasis. In addition, movement of Ca2+ from the bone as a result of osteoclastic bone resorption also provides a large Ca2+ supply in Ca2+ homeostasis; however, the system controlling Ca2+ homeostasis in osteoclasts has not been fully identified. Transient receptor potential vanilloid (TRPV) 4 mediates Ca2+ influx during the late stage of osteoclast differentiation, thereby regulating the Ca2+ signaling essential for cellular events during osteoclast differentiation; however, the system-modifying effect of TRPV4 activity should be determined. Furthermore, it remains unknown how local Ca2+ metabolism participates in systemic Ca2+ homeostasis through bone remodeling. New insights are therefore required to understand this issue.