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Principal Investigator: Zhaoyang Liu
Organization: UNIVERSITY OF SOUTHERN CALIFORNIA
Fiscal Year: 2024
Award: $236,917
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary
Osteoarthritis (OA) is the most common form of degenerative joint disease affecting millions of people
worldwide and lead to a tremendous financial burden. Currently there are no disease modifying therapies
available for OA, due to limited understanding of the genetic factors and pathways underling OA progression.
Therefore, a comprehensive understanding of signaling pathways driving the pathogenesis of OA will motivate
innovation for early diagnosis and disease modifying therapeutics. This proposal will further the molecular
characterization of a genetic mutant mouse of the Adhesion G protein-coupled receptor G6 (Adgrg6) gene.
ADGRG6 is enriched in articular cartilage in human and mouse, and we have demonstrated its involvement in
human OA. Loss of Adgrg6 in the articular cartilage in mouse leads to OA-like joint pathology, and
dysregulation of both cAMP and STAT3 signaling pathway. Interestingly, cAMP signaling is previously
indicated to drive chondroprotective mechanisms, and STAT3 activation is associated with OA development in
human. Based on these novel findings, we hypothesize that homeostasis of articular cartilage requires precise
regulation of both cAMP and STAT3 signaling. This hypothesis will be tested under three specific aims:
1. We will specifically activate cAMP signaling in articular cartilage using a novel Gs-coupled DREADD
mouse, and determine the transcriptional network regulated by cAMP signaling. We will determine the
cellular effectors of cAMP signaling during OA development in Adgrg6 mutant mice and in post-traumatic
mouse model of OA.
2. We will determine the downstream effectors of STAT3-mediated signaling during OA progression using the
post-traumatic mouse model of OA by analysis of STAT3 dependent gene regulation.
3. We will determine the efficacy of targeting STAT3 and cAMP signaling pathways for treatment of OA-like
joint pathology using the post-traumatic mouse model of OA. We will utilize innovative pharmaceutical
approaches for localized, slow-release delivery of disease modifying therapies targeting these pathways.
Taken together, this proposed study will utilize mouse genetics, combined with modern genomics and
pharmaceutic approaches to define the role of cAMP and STAT3 signaling in articular cartilage homeostasis
and OA pathogenesis, which may accelerate our diagnosis and treatment of human OA.
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