# Gas-Hedgehog signaling in intramembranous bone formation and expansion

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $471,593

## Abstract

Gαs-Hedgehog signaling in intramembranous bone formation and expansion
Summary
The development of a functional skeletal system requires tight spatial and temporal control of osteoblast
differentiation and maturation. How osteoblast cells are induced at the outset of bone development is a central
question in understanding the organizational principles underpinning a functional skeletal system. Extraskeletal
or heterotopic ossification (HO) occurs as a common complication of trauma or in rare genetic disorders and
can be disabling and lethal. The precise cellular and molecular mechanisms underlying HO are not clear.
Research in our lab has provided insights into the molecular and cellular regulation of bone development and
recently we have identified a novel Gαs-Hedgehog (Hh) signaling axis that critically regulates ectopic
osteoblast differentiation in progressive osseous heteroplasia (POH). POH is a rare human genetic disease in
which HO occurs predominantly through an intramembranous process and progresses from subcutaneous
tissue into skeletal muscle and deep connective tissues. POH is caused by inactivating mutations in GNAS
that encodes Gαs that transduces signals from G protein coupled receptors (GPCRs). We have found that loss
of Gαs function in POH leads to ligand-independent activation of Hh signaling, which in turn induces osteoblast
differentiation of mesenchyme cells in soft tissues, whereas activation of Gαs signaling leads to Wnt/β-catenin
signaling upregulation and reduced osteoblast differentiation in the human condition of fibrous dysplasia (FD).
We have further observed in our preliminary studies that ectopic bone formation and expansion in POH bare
cellular and molecular similarities to craniofacial bone development. Here we will build upon our unique
perspectives and test our central hypothesis: Hh signaling activation by Gαs inhibition induces
osteoblast differentiation during intramembranous bone formation and recruits wild type cells into
ectopic bone during progressive ossification in POH. In Specific Aim 1, we will investigate the role of
Gαs-regulated Hh signaling during formation and growth of intramembranous bone. In Specific Aim 2,
we will extend findings in normal craniofacial bone growth to ectopic bone in POH. We will test our
hypothesis that ectopic bone in POH expands by inducing a suture-like tissue where wild type
osteogenic mesenchyme stem cells reside. Our proposed studies will provide an unprecedented level of
insight in acquired HO and the regulation of osteoblast differentiation under both physiological and pathological
conditions. Knowledge gained here from the mouse models of POH will be readily translatable to human
diseases such as POH, acquired HO, FD, craniosynostosis and osteoporosis. We anticipate that our findings
will have broad significance with respect to cell-fate specification and reprogramming processes during
development, repair, and regeneration of many other organ systems where Gαs-Hh and ...

## Key facts

- **NIH application ID:** 9977003
- **Project number:** 5R01DE025866-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Yingzi Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $471,593
- **Award type:** 5
- **Project period:** 2016-07-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977003

## Citation

> US National Institutes of Health, RePORTER application 9977003, Gas-Hedgehog signaling in intramembranous bone formation and expansion (5R01DE025866-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9977003. Licensed CC0.

---

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