# HIFs in osteocytes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $445,303

## Abstract

Project Summary
 There is a critical socioeconomic and medical need for anabolic therapies capable of replacing lost bone
mass in diseases such as osteoporosis. Humans and mice with striking high bone mass (HBM) can aid in the
identification of novel mechanisms to promote osteoanabolism. Notable examples include activating mutations
in the Wnt co-receptor Lrp5 and individuals with sclerosteosis (decreased SOST expression).
 We have found that deletion of Vhl in osteocytes but not osteoblasts (Dmp1-cre;Vhlf/f) produces a robust
skeletal phenotype, characterized by dramatic increases in both cortical and trabecular microarchitecture
compared to age-matched wild-type mice. Vhl targets hypoxia inducible factor-alpha (HIF-a) subunits for
ubiquitination and subsequent proteasomal degradation under normoxic conditions, and is considered a
master regulator of HIF activity. In contrast to previous work deleting Hif1a in osteoblasts, we do not observe a
reciprocal, low bone mass phenotype in osteocytes lacking Hif1a. Our data suggest that osteocytes may only
require HIF-2a to transduce Vhl signaling, presenting new possibilities to identify and exploit yet-unknown
pathways in osteocytes, that could be harnessed to improve bone health.
 It is not that surprising that osteoblasts and osteocytes might use different signaling machinery to
transduce a particular signal, as a multitude of genes undergo upregulation or downregulation during the
osteoblast-to-osteocyte transition. Increasing evidence shows that while HIF-1a and HIF-2a are both
expressed in bone cells, their stability is differentially regulated, and they induce transcription of distinct gene
targets. While much attention has focused on the role of HIF-1a in bone, very little is known about HIF-2a.
 Our long-term goal is to elucidate HIF-a isoform contribution to skeletal development, HIF-a isoform
functional redundancy, integration with Wnt/b-catenin signaling, and if manipulation of Vhl/HIF-a expression
prevents ovariectomy (OVX)-induced bone loss. Our overall hypothesis is that osteocytes require HIF-2a,
rather than HIF-1a, to mediate effects on the skeleton. Within, we will evaluate the fundamental requirement of
OCY HIF-2a in longitudinal bone growth, as well as HIF-a isoform specificity to recapitulate and maintain the
Vhl cKO HBM phenotype (Aim 1), the epistatic relationship of b-catenin in the HBM phenotype of Vhl cKO
mice (Aim 2), and the utility of targeting HIF-a for improving bone properties in an OVX mouse model (Aim 3).
 These studies will define the role of HIF-a-dependent functions of Vhl in osteocytes that drive acquisition of
HBM. Understanding these signaling pathways may allow identification of novel therapeutic targets leading to
bone accrual and reversing the osteoporosis that accompanies aging and menopause. Doing so will alleviate
the costs and associated quality of life issues that result in the inevitable fractures that are so common, without
the associated complications t...

## Key facts

- **NIH application ID:** 9903227
- **Project number:** 5R01AR073772-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** DAMIAN C GENETOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,303
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903227

## Citation

> US National Institutes of Health, RePORTER application 9903227, HIFs in osteocytes (5R01AR073772-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9903227. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*