Elucidating the role of GS-gpcr signaling at the bone-vascular interface

The National Institute of Dental and Craniofacial Research awarded Northern California Institute For Research And Education, Inc. $499,022 on August 15, 2026, to conduct research elucidating the role of GS-GPCR signaling at the bone-vascular interface under the Oral Diseases and Disorders Research program (CFDA 93.121).

The project investigates molecular mechanisms by which GS-GPCR signaling in endothelial and perivascular cells contributes to osteogenesis and fibrosis, using fibrous dysplasia of the bone as a disease model. The research addresses a gap in current understanding: while GS-GPCR activation in osteogenic lineages is well-established as a driver of bone formation and an effective treatment strategy for osteoporosis, fractures, and skeletal dysplasias via recombinant parathyroid hormone, the role of this signaling pathway in non-osteogenic vascular cells within the bone niche remains poorly understood. Single-cell RNA sequencing data from human fibrous dysplasia bone lesions revealed that endothelial and perivascular cells harbor mutations and express altered, fibrotic transcriptomes, suggesting that vascular cell lineages may contribute to the dramatic disease phenotype and may regulate bone formation more broadly.

Place of performance is San Francisco, California. The period of performance runs from August 15, 2026 through August 14, 2027. The award is a Project Grant, an assistance type supporting hypothesis-driven research under peer review.

Abstract

Skeletal diseases contribute significantly to morbidity, yet limited therapies exist for building new bone. Understanding the molecular mechanisms driving bone formation is critical for improving skeletal health across the lifespan. GS-gpcr signaling is a major driver of bone formation, and activating this pathway using recombinant parathyroid hormone (PTH) is an effective treatment strategy for osteoporosis, fractures, and skeletal dysplasias. The anabolic effect of GS-gpcr activation in osteogenic lineages is well-established, but its role in non-osteogenic cells in the bone niche is poorly understood. There is compelling evidence that cells comprising the bone vasculature play an integral role in skeletal development, maintenance, and repair, yet the role of GS-gpcr signaling in these lineages and the effect on osteogenesis has not been studied. Fibrous dysplasia of the bone (FD) is a prototypical disease of constitutive GS-gpcr signaling that leads to expansile, fibrotic bone lesions and massive trabecular bone growth. We and others have used FD as a disease model to delineate the mechanisms by which GS-gpcr activation in osteogenic lineages drives bone formation. The long- standing paradigm has been that GS-gpcr signaling in osteoprogenitors drives fibrosis and aberrant osteogenesis in FD. Single-cell RNA sequencing data from human FD bone lesions shows that in addition to osteogenic lineages, endothelial and perivascular cells also harbor GNASR201H/C mutations and express an altered, fibrotic transcriptome. This unexpected finding suggests that GS-gpcr signaling in vascular cell lineages may contribute to the dramatic FD phenotype and may regulate bone formation more broadly. The overall objective of this proposal is to elucidate the molecular mechanisms by which GS-gpcr signaling in endothelial and perivascular cells contribute to osteogenesis and fibrosis, using FD as a disease model. Our central hypothesis is that GS-gpcr signaling in endothelial and perivascular lineages activates critical signaling pathways downstream of GSA, including vegf, WNT/ B-catenin and TGF B/BMP that promote fibrosis and osteogenesis. To test this hypothesis, we implement human induced pluripotent stem cell (HIPSC) models, primary human cells and tissue, and murine models to elucidate the role of GS-gpcr signaling at the bone- vascular interface. Detailed knowledge of the signaling pathways activated at the bone-vascular interface will help elucidate the mechanisms by which GS-gpcr signaling in non-skeletal lineages contribute to bone formation. This knowledge can then be leveraged to develop new therapeutics for diseases of impaired osteogenesis, including osteoporosis, fracture repair, and skeletal dysplasias.