Neuropilin 2 in osteoblasts regulates trabecular bone mass in male mice.

INTRODUCTION

Neuropilin 2 (NRP2) mediates the effects of class 3 semaphorins and vascular endothelial growth factor and is implicated in axonal guidance and angiogenesis. Moreover, NRP2 expression is suggested to be involved in the regulation of bone homeostasis. Indeed, osteoblasts and osteoclasts express NRP2 and male and female global knockout mice have a reduced bone mass accompanied by reduced osteoblast and increased osteoclast counts.

METHODS

We first examined the effect of the calciotropic hormone 1,25-dihydroxyvitamin D [1,25(OH)D] on transcription in osteoblasts. We next generated mice with a conditional deletion of in the osteoblast cell lineage under control of the paired related homeobox 1 promoter and mice with a conditional knockdown in osteoclasts under control of the Lysozyme promoter. Mice were examined under basal conditions or after treatment with either the bone anabolic vitamin D analog WY 1048 or with 1,25(OH)D.

RESULTS AND DISCUSSION

We show that expression is induced by 1,25(OH)D in osteoblasts and is associated with enrichment of the vitamin D receptor in an intronic region of the Nrp2 gene. In male mice, conditional deletion of in osteoblast precursors and mature osteoblasts recapitulated the bone phenotype of global knockout mice, with a reduced cortical cross-sectional tissue area and lower trabecular bone content. However, female mice with reduced osteoblastic expression display a reduced cross-sectional tissue area but have a normal trabecular bone mass. Treatment with the vitamin D analog WY 1048 (0.4 μg/kg/d, 14 days, ip) resulted in a similar increase in bone mass in both genotypes and genders. Deleting from the osteoclast lineage did not result in a bone phenotype, even though osteoclastogenesis of hematopoietic cells derived from mutant mice was significantly increased. Moreover, treatment with a high dose of 1,25(OH)D (0.5 μg/kg/d, 6 days, ip), to induce osteoclast-mediated bone resorption, resulted in a similar reduction in trabecular and cortical bone mass. In conclusion, osteoblastic expression is suggested to regulate bone homeostasis in a sex-specific manner.