Integrated View on the Role of Vitamin D Actions on Bone and Growth Plate Homeostasis

Abstract

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.

Keywords: ANIMAL MODELS; CELL/TISSUE SIGNALING; CELLS OF BONE; CHONDROCYTE AND CARTILAGE BIOLOGY; DISORDERS OF CALCIUM/PHOSPHATE METABOLISM; ENDOCRINE PATHWAYS; GENETIC ANIMAL MODELS; PTH/VIT D/FGF23.

Fig 1

Overview of skeletal cell types in which Vdr expression is targeted. (Figure created with BioRender.com.)

Fig 2

During a positive calcium balance (left panel), normal serum calcium concentrations allow proper bone mineralization. Transgenic models with Vdr inactivation in osteoprogenitors (Osx‐Cre^{( 51 )}) or in mature osteoblasts and osteocytes (Dmp1‐Cre^{( 26 )}) display normal mineral and bone homeostasis. Vdr knockdown in immature osteoblasts (Col1a1‐Cre^{( 49 )}) induces bone mass, whereas Vdr overexpression in mature osteoblasts (Osteocalcin‐Cre^{( 48} , ^{50 )}) also leads to an elevated bone mass. Vdr inactivation in osteoclast precursors (LysM‐Cre^{( 57 )}) does not affect bone homeostasis, whereas Vdr‐silencing in mature osteoclasts (Ctsk‐Cre) has either no effect^{( 51 )} or leads to a slight reduction in bone mass.^{( 58 )} During a negative calcium balance (right panel), insufficient intestinal calcium absorption leads to increased PTH and 1,25(OH)₂D₃ levels, which stimulate RANKL expression by osteoblasts and enhance bone resorption.^{( 52 )} Moreover, 1,25(OH)₂D₃ inhibits bone mineralization by directly inducing the expression of mineralization inhibitors.^{( 26 )} Elevated resorption and decreased mineralization both contribute to the maintenance of normocalcemia. Mice with selective Vdr knockdown in mature osteoclasts (Ctsk‐Cre^{( 59 )}) experience a greater bone loss during a negative calcium balance. (Figure created with BioRender.com.)