# Investigating the Role of Gpr126 in cartilage for Intervertebral Disc and Spine Homeostasis

> **NIH NIH F32** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $70,430

## Abstract

Project Summary
Adolescent idiopathic scoliosis (AIS) is the most common pediatric musculoskeletal disease, affecting 3% of
children worldwide. The pathophysiology and molecular mechanisms of AIS remain poorly understood,
however recent population studies have begun to identify associated risk loci, including GPR126. We have
generated the first mouse model of AIS by knocking out Gpr126 in osteochondral progenitor cells, which give
rise to both bone and cartilage tissues of the spine. Close examination of these mice uncovered defects in
intervertebral discs (IVDs) and changes in the expression of well-established anabolic and catabolic factors
important for IVD homeostasis prior to AIS onset. Recently, we find that loss of Gpr126 in osteoblast lineages
does not generate scoliosis or bone defects, ruling out the role of Gpr126 in bone for AIS. In contrast, loss of
Gpr126 in cartilage resulted in mild scoliosis in young mice that could progress in severity at later time point.
Together these observations provide the foundation for the central hypothesis of this application: GPR126 has
a critical role in cartilage for IVD homeostasis and spine stability. This hypothesis will be tested under two
specific aims. (1) To determine the structural and mechanical changes of the IVD during the natural history of
AIS and identify the molecular functions of Gpr126 for spine stability. We find no role for Gpr126 in bone
development or homeostasis, however we do observe that loss of Gpr126 in cartilage resulted in IVD defects
prior to and following the onset of scoliosis. It remains to be determined whether these defects are primary or
secondary causes of scoliosis. We hypothesis that defects in the IVDs might be primary to scoliosis in our AIS
mouse model. To test this hypothesis, we will determine the precise structural and mechanical changes of the
IVDs as well as vetebra bodies during the natural history of AIS using contrast-enhanced 3D microCT imaging
and mechanical testing. We will also comprehensively characterize cellular and molecular changes of the IVD
using unbiased "omics" approaches, including RNA-seq, ChIP-seq and mass spectrometry performed on
primary IVDs isolated prior to and following the onset of AIS. (2) To determine whether inflammation is a major
driver of AIS and IVD degeneration following loss of Gpr126. Our preliminary results show that loss of Gpr126
in cartilage leads to severe IVD defects and abnormally activated IL-6/Stat3 signaling prior and after the IVD
degeneration. To test whether Gpr126 interacts with the IL-6/Stat3 signaling to modulate cartilage development
and homeostasis, we will utilize our cartilage-specific Gpr126 knockout mouse and genetically test if loss of
Stat3 will ameliorate disc degeneration and scoliosis. We will complement this genetic approach using a
pharmacological approach to administer Stat3 inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) to
determine whether blocking these inflammatory pathway...

## Key facts

- **NIH application ID:** 9879628
- **Project number:** 5F32AR073648-03
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Zhaoyang Liu
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $70,430
- **Award type:** 5
- **Project period:** 2018-03-14 → 2021-03-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879628

## Citation

> US National Institutes of Health, RePORTER application 9879628, Investigating the Role of Gpr126 in cartilage for Intervertebral Disc and Spine Homeostasis (5F32AR073648-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879628. Licensed CC0.

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