Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss

Postmenopausal osteoporosis is characterized by a reduction in the numbers of sinusoidal and arterial capillaries in the bone marrow and reduced bone perfusion suggesting a role of vascular component in the pathogenesis of osteoporosis. Previous studies have shown that bone formation and angiogenesis are positively coupled through activation of the hypoxia inducible factor (HIF1α) signaling pathway. Therefore, we hypothesized that mice with increased angiogenesis and osteogenesis due to activation of the HIF signaling pathway in osteoblasts, via osteoblast specific disruption of HIF degrading protein von Hippel-Lindau (VHL) (ΔVhl), are protected from ovariectomy induced bone loss. ΔVhl mice and control littermates were ovariectomized or sham operated and four weeks later bone quality was evaluated along with blood vessel formation. Trabecular and cortical bone volume was strikingly increased in ΔVhl mice along with blood vessel formation as compared to control littermates. In control mice, ovariectomy significantly decreased bone mineral density, deteriorated bone microarchitecture, and decreased mechanical strength compared to the sham operated control mice. This was accompanied with a significant decrease in blood vessel volume and expressions of HIF1α, HIF2α, and VEGF proteins at the distal femur in ovariectomized control mice. In contrast, ovariectomy in ΔVhl mice had absolutely no effect on either the blood vessel formation or the bone structural and mechanical quality parameters. These data indicate that activation of HIF signaling pathway in osteoblasts may prevent estrogen deficiency-induced bone loss and decrease in blood vessels in bone marrow.