Bone Abstracts

Prolyl hydroxylase 2 (PHD2) regulates hypoxia-inducible factor α (HIFα) transcription factors and thus, erythropoietin (EPO) production. Under normoxic conditions, HIFα is constantly inactivated through hydroxylation by PHD2. Due to the embryonic lethality of PHD2 knock-out mice, its precise role in erythropoiesis and tissue homeostasis has long remained unknown. Recently, we generated a conditional knock-out (cKO) mouse lacking PHD2 in EPO-producing cells. These mice have high levels of EPO and an increased hematocrit, which is dependent on HIF2α. In this study, we determined the role of PHD2 in bone.

Total, trabecular, and cortical bone density at the femur was significantly decreased by 12, 20, and 5% in cKO as compared to WT mice. Results were confirmed using histomorphometry, showing a 38% decrease in bone volume in the tibia, accompanied by microarchitectural changes including fewer trabeculae (−33%) and an increased trabecular spacing (+59%) in cKO mice. Bone resorption was not affected, as determined using serum levels of C-terminal telopeptide of type I collagen and tartrate-resistant acid phosphatase, and the histological evaluation of osteoclasts. In contrast, osteoblasts function was severely impaired. Serum levels of procollagen type I N-terminal propeptide and osteocalcin were decreased by 30–40% in cKO mice. In line with that, the mineralized surface, the mineral apposition rate, the bone formation rate, and the osteoblast surface were reduced by 35–50%. To further pinpoint which downstream signals are involved, we used PHD2/HIF1α (P2/H1) and PHD2/HIF2α (P2H2) double-knock-out (DKO) mice. While P2/H1 DKO mice, which also have high EPO levels, showed a similar bone phenotype as cKO, including decreased bone density and bone formation, bone density was restored in P2/H2 DKO mice, which have normal EPO levels.

Thus, these data identify PHD2 as a novel regulator of osteohematology, by controlling erythropoiesis and bone homeostasis.