HIF2 in Bone Mass Accrual and Homeostasis
We are studying how the loss of HIF2 in mesenchymal progenitors increases bone mass and its translational implications
We demonstrated that loss of HIF2 in mesenchymal progenitors increases bone mass accrual by promoting bone formation without affecting bone resorption. HIF2 is another crucial mediator of the cellular adaptation to hypoxia. We are currently investigating whether pharmacological inhibition of HIF2 phenocopies the genetic experiment. HIF2 can be selectively inhibited by small molecules that are in clinical trials in patients with renal carcinoma. Inhibiting HIF2 could represent a therapeutic approach for treating low bone mass observed in chronic diseases, osteoporosis, or aging. Additionally, we are using unbiased approaches to establish how the loss of osteoblastic HIF2 promotes bone formation (R01 AR073022, Dr. Schipani PI).
Hypoxia-inducible factor 2α is a negative regulator of osteoblastogenesis and bone mass accrualView Publication
Osteoblasts, which are the bone-forming cells, operate in a hypoxic environment. The transcription factors hypoxia-inducible factor-1α (HIF1) and HIF2 are key mediators of the cellular response to hypoxia. Both are expressed in osteoblasts. HIF1 is known to be a positive regulator of bone formation. Conversely, the role of HIF2 in the control osteoblast biology is still poorly understood. In this study, we used mouse genetics to demonstrate that HIF2 is an inhibitor of osteoblastogenesis and bone mass accrual. Moreover, we provided evidence that HIF2 impairs osteoblast differentiation at least in part, by upregulating the transcription factor Sox9. Our findings constitute a paradigm shift, as activation of the hypoxia-signaling pathway has traditionally been associated with increased bone formation through HIF1. Inhibiting HIF2 could thus represent a therapeutic approach for the treatment of the low bone mass observed in chronic diseases, osteoporosis, or aging.
The HIF Signaling Pathway in Osteoblasts Directly Modulates Erythropoiesis through the Production of EPOView Publication
Osteoblasts are an important component of the hematopoietic microenvironment in bone. However, the mechanisms by which osteoblasts control hematopoiesis remain unknown. We show that augmented HIF signaling in osteoprogenitors results in HSC niche expansion associated with selective expansion of the erythroid lineage. Increased red blood cell production occurred in an EPO-dependent manner with increased EPO expression in bone and suppressed EPO expression in the kidney. In contrast, inactivation of HIF in osteoprogenitors reduced EPO expression in bone. Importantly, augmented HIF activity in osteoprogenitors protected mice from stress-induced anemia. Pharmacologic or genetic inhibition of prolyl hydroxylases1/2/3 in osteoprogenitors elevated EPO expression in bone and increased hematocrit. These data reveal an unexpected role for osteoblasts in the production of EPO and modulation of erythropoiesis. Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment.