# HIF-2alpha, a Novel Regulator of Osteoblastogenesis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $346,242

## Abstract

ABSTRACT
 Advancing our understanding of the mechanisms that control bone mass and osteoblast differentiation is crucial
to unveil the pathogenesis of skeletal diseases and identify therapeutical approaches for their treatment.
Osteoblastic cells operate in a low oxygen (hypoxic) environment. The transcription factors Hypoxia Inducible
Factor-1a (HIF1) and HIF2 are critical mediators of the cellular response to hypoxia. Both transcription factors
are expressed in cells of the osteoblast lineage. HIF1 was reported to be a positive regulator of bone formation
and osteoblast differentiation. Conversely, the role of HIF2 in the control of bone mass and osteoblast biology is
still poorly understood. We recently generated mutant mice carrying loss-of-function and gain-of-function
mutations of HIF2 in mesenchymal progenitors of the limb bud by using PRX1-Cre. Preliminary analysis of these
mutant mice suggested that HIF2 is a negative regulator of osteoblastogenesis and bone formation through a
direct action on cells on the osteoblast lineage. Mechanistically, we gathered preliminary evidence that Sox9,
which is emerging as a negative regulator of osteoblast differentiation, is likely to mediate the HIF2-dependent
impairment of osteoblastogenesis. Our findings constitute a paradigm shift as activation of the HIF signaling
pathway has been associated with increased, rather than decreased, osteoblast activity. Moreover, they imply
that, as in other cell types, HIF1 and HIF2 have opposing functions in osteoblastic cells. Also, our preliminary
data showed that loss of HIF2 in mesenchymal progenitors of the limb bud increases bone mass in both
trabecular and cortical bone. HIF2 can be selectively inhibited by small molecules, some of which are currently
in clinical trials in patients carrying pathologies associated with high levels of HIF2 activity such as clear cell
renal carcinoma. Therefore, determining whether and how HIF2 controls osteoblastogenesis and bone mass
not only will expand and deepen our understanding of the role of the hypoxia signaling pathway in the skeleton
but could also provide a novel target for the treatment of low bone mass seen in chronic diseases, osteoporosis
and with aging. In this proposal, we thus seek to demonstrate that osteoblastic HIF2 regulates bone mass during
skeletal development and in adulthood (Aim 1). Moreover, we will establish whether osteoblastic HIF2 controls
osteoblastogenesis through a direct action on mesenchymal progenitors and in a Sox9-dependent manner (Aim
2).
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## Key facts

- **NIH application ID:** 10320694
- **Project number:** 7R01AR073022-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ernestina Schipani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,242
- **Award type:** 7
- **Project period:** 2019-01-11 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320694

## Citation

> US National Institutes of Health, RePORTER application 10320694, HIF-2alpha, a Novel Regulator of Osteoblastogenesis (7R01AR073022-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320694. Licensed CC0.

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