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

Lieve Verlinden,Geert Carmeliet

doi:10.1002/jbm4.10577

Abstract

ABSTRACT1,25(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.

Highlights

The hormonally active form of vitamin D3, 1,25(OH)2D3, is an important mediator of mineral and bone homeostasis. 1,25 (OH)2D3, primarily produced in the kidneys, exerts its effects through the vitamin D receptor (VDR), which is most abundantly expressed in tissues involved in the maintenance of mineral and bone homeostasis, such as the parathyroid glands, intestine, kidney, and bone.[1]. Mutations in the VDR gene that result in a defective receptor lead to the development of vitamin D-dependent rickets type 2, an autosomal recessive disorder characterized by the early onset of rickets, hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia.[2]
In response to the reduced intestinal calcium absorption in these mice, circulating levels of parathyroid hormone (PTH) and 1,25 (OH)2D3 are increased, which enhance bone resorption and suppress bone matrix mineralization. Both processes contribute to the maintenance of normal serum calcium levels, as the increased bone resorption releases calcium from the bone, whereas the suppressed bone mineralization prevents calcium incorporation in the bone. These findings indicate that the maintenance of normocalcemia occurs at the expense of skeletal integrity.[26]. Interestingly, mice with Vdr inactivation in the distal intestine reveal that the large intestine significantly contributes to whole-body calcium homeostasis.[27]. In agreement, transgenic expression of human VDR exclusively in the ileum, caecum, and colon of Vdr null mice prevents abnormalities in calcium and bone homeostasis, confirming the essential role of VDR-mediated calcium absorption in the distal gastrointestinal tract.[12,28] Of note, villin-driven overexpression of the VDR in the intestine of wild-type mice does not improve the intestinal response to 1,25(OH)2D3 nor does it prevent the bone loss when mice are fed a low calcium diet, indicating that supraphysiological intestinal VDR levels do not provide additional benefit.[29]
The role of VDR signaling in mature osteoblasts and osteocytes is studied by targeted Vdr knockdown (90%) under control of the dentin matrix protein 1 (Dmp1) promoter (Dmp-Vdr-cKO mice).(26) Mineral and bone homeostasis is not disturbed in Dmp-Vdr-cKO mice as evidenced by normal serum levels of calcium, phosphate, and 1,25(OH)2D3 and normal cortical and trabecular bone mass

Summary

Introduction

The hormonally active form of vitamin D3, 1,25(OH)2D3, is an important mediator of mineral and bone homeostasis. 1,25 (OH)2D3, primarily produced in the kidneys, exerts its effects through the vitamin D receptor (VDR), which is most abundantly expressed in tissues involved in the maintenance of mineral and bone homeostasis, such as the parathyroid glands, intestine, kidney, and bone.[1]. In response to the reduced intestinal calcium absorption in these mice, circulating levels of PTH and 1,25 (OH)2D3 are increased, which enhance bone resorption and suppress bone matrix mineralization.

Results

Conclusion