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Understanding the Role of T Cell Subsets in Osteogenesis Imperfecta

Award Number: R01AR086485
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Understanding the Role of T Cell Subsets in Osteogenesis Imperfecta - Abstract Osteogenesis imperfecta (OI), an autosomal dominant disorder, is the most common hereditary bone disease. OI is characterized by mild to a severe reduction in the quantity of bone matrix that leads to repeated fractures and bone deformity. In the United States, the incidence of OI is estimated to be 1 per 20,000 live births. At present, there is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture. Long- term treatment with drugs has side effects; therefore, several strategies are being tested experimentally in OI to enhance bone remodeling. Recently the role of T lymphocytes in bone remodeling has been gaining attention. It has been demonstrated that T cells may play a role in bone regeneration after a fracture. However, whether T cells play a role in OI has never been investigated before. For our studies, we used the B6C3Fe a/a-Col1a2oim/J (oim) model of OI, which resembles Type III OI, a non-lethal but severe form of OI. Our preliminary data, characterizing the T cells from the OI mice demonstrated that splenic T cells derived from oim/oim mouse exhibited a more activated phenotype than wild type (WT) T cells, which also correlated with higher secretion of effector cytokines, IFN- and TNF-α. Furthermore, we observed a reduced number of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in oim/oim. Treg Transplantation in OI mice restored T cell tolerance and improved bone parameters. Our data also shows that reduction in the number of Tregs in OI mice is due to reduced BMP and YAP signaling in naïve T cells, pointing towards the involvement of BMPR1α. Thus, we hypothesize that “reduced BMP and YAP signaling in OI T cells directly correlates to the lower number of Tregs and increased activated phenotype of effector T cells. Consequently, quantitative restoration of Tregs in OI inhibits the pro- inflammatory cytokines and leads to better bone formation”. Aim 1 will determine the cause of the decreased Treg numbers in OI by analyzing the role that BMP signaling plays in this reduction, especially the role of BMPR1α and downstream regulation by Smads and YAP. The immune profile in peripheral blood of OI patients will also be determined. Aim 2 will define the mechanism by which Tregs affect osteoblasts and osteoclasts. This aim will examine whether Tregs act through the secreted factor, IL-10, which acts along with Cox-2 and Sfrp-2 to increase osteoblastic differentiation and decrease osteoclast numbers. Aim 3 will optimize the Treg transplantation in murine models of OI. Transplantation of Tregs, especially OI Tregs (auto transplantation), will be examined in different models of OI. Use to sodium butyrate, IL-10 and anti-Sfrp-2 antibody will also be studied. Understanding the contribution of Tregs to osteogenesis in OI could help develop new avenues of cellular immunotherapy for OI, thereby providing potential new translational approaches in the treatment of OI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,990,143 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/17/2026	NEW	$1,990,143
														Subtotal = $1,990,143

Grand Total All Awards = $1,990,143

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Understanding the Role of T Cell Subsets in Osteogenesis Imperfecta

Award Number: R01AR086485

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/18/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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