Vitamin D Receptor in Osteoblasts Is a Negative Regulator of Bone Mass Control

Abstract

The physiological and beneficial actions of vitamin D in bone health have been experimentally and clinically proven in mammals. The active form of vitamin D [1α,25(OH)2D3] binds and activates its specific nuclear receptor, the vitamin D receptor (VDR). Activated VDR prevents the release of calcium from its storage in bone to serum by stimulating intestinal calcium absorption and renal reabsorption. However, the direct action of VDR in bone tissue is poorly understood because serum Ca2+ homeostasis is maintained through tightly regulated ion transport by the kidney, intestine, and bone. In addition, conventional genetic approaches using VDR knockout (VDR-KO, VDR−/−) mice could not identify VDR action in bone because of the animals' systemic defects in calcium metabolism. In this study, we report that systemic VDR heterozygous KO (VDR+/L−) mice generated with the Cre/loxP system as well as conventional VDR heterozygotes (VDR+/−) showed increased bone mass in radiological assessments. Because mineral metabolism parameters were unaltered in both types of mice, these bone phenotypes imply that skeletal VDR plays a role in bone mass regulation. To confirm this assumption, osteoblast-specific VDR-KO (VDRΔOb/ΔOb) mice were generated with 2.3 kb α1(I)-collagen promoter-Cre transgenic mice. They showed a bone mass increase without any dysregulation of mineral metabolism. Although bone formation parameters were not affected in bone histomorphometry, bone resorption was obviously reduced in VDRΔOb/ΔOb mice because of decreased expression of receptor activator of nuclear factor kappa-B ligand (an essential molecule in osteoclastogenesis) in VDRΔOb/ΔOb osteoblasts. These findings establish that VDR in osteoblasts is a negative regulator of bone mass control.

Expression of Fibroblast Growth Factor 23, Vitamin D Receptor, and Sclerostin in Bone Tissue from Hypercalciuric Stone Formers

“…With a few exceptions (27,28), most of the previous histomorphometric studies have shown increased bone resorption among hypercalciuric patients (3,5,7,8). Vitamin D-induced osteoclastogenesis seems to be accomplished through a VDR-mediated increase in RANKL expression in osteoblasts (36).…”

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

“…The role of VDR signaling in bone cells during a positive calcium balance is still not fully elucidated, but the specific effects likely depend on the osteoblast differentiation stage (FIGURE 6). VDR signaling in osteoprogenitors and osteoblasts has a positive effect on osteoclast formation and bone resorption and thus negatively regulates bone mass, as shown by Vdr inactivation in mice using the collagen type I promoter which resulted in increased bone mass (501). On the other hand, VDR activity in more mature osteoblasts has anabolic and anticatabolic activity and increases bone mass, as evidenced by Vdr overexpression using the osteocalcin promotor (29, 157).…”

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

“…Moreover, ablating Vdr or Cyp27b1 from cells within the skeleton does not cause rickets either. The skeleton is normal if Vdr is selectively ablated from chondrocytes, mature osteoblasts, or osteocytes (375,421), and a high bone mass phenotype with reduced resorptive surfaces occurs when Vdr is ablated from osteoblasts (750). Ablating Cyp27b1 from chondrocytes does not reproduce the rachitic growth plate, whereas low phosphorus will cause the widened, irregular growth plate (466).…”