1,25(OH)2D3, the biologically active form of
vitamin D3, is a major regulator of
mineral and bone homeostasis and exerts its actions through binding to the
vitamin D receptor (VDR), a
ligand-activated
transcription factor that can directly modulate gene expression in
vitamin D-target tissues such as the intestine, kidney, and bone. Inactivating VDR mutations or
vitamin D deficiency during development results in
rickets,
hypocalcemia,
secondary hyperparathyroidism, and
hypophosphatemia, pointing to the critical role of 1,25(OH)2D3-induced signaling in the maintenance of
mineral homeostasis and skeletal health.
1,25(OH)2D3 is a potent stimulator of VDR-mediated intestinal
calcium absorption, thus increasing the availability of
calcium required for proper bone mineralization. However, when intestinal
calcium absorption is impaired, renal
calcium reabsorption is increased and
calcium is mobilized from the bone to preserve normocalcemia. Multiple cell types within bone express the VDR, thereby allowing
1,25(OH)2D3 to directly affect bone homeostasis. In this review, we will discuss different transgenic mouse models with either Vdr deletion or overexpression in chondrocytes, osteoblasts, osteocytes, or osteoclasts to delineate the direct effects of
1,25(OH)2D3 on bone homeostasis. We will address the bone cell type-specific effects of
1,25(OH)2D3 in conditions of a positive
calcium balance, where the amount of (re)absorbed
calcium equals or exceeds fecal and renal
calcium losses, as well as during a negative
calcium balance, due to selective Vdr knockdown in the intestine or triggered by a low
calcium diet. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and
Mineral Research.