Tuesday, January 13, 2026 1/13/2026

Targeting jmjd3 mitigates heterotopic ossification

Award Number: R01AR079863
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Targeting jmjd3 mitigates heterotopic ossification - PROJECT SUMMARY/ABSTRACT Heterotopic ossification (HO) is the pathologic formation of extra-skeletal that is always preceded by an inflammatory insult and occurs in ~20% of patients after hip arthroplasty, burns or musculoskeletal injury. Currently, no therapeutics or physical therapy-based protocols exist to prevent or treat HO. In this regard, there is a void in our understanding of the molecular mechanisms underlying HO formation and progression. We present data that the histone demethylase, JMJD3, is increased in HO macrophages (Mφs) resulting in persistent production of transforming growth factor-beta (TGFꞵ1) at the HO injury site. This excess TGFꞵ1 causes aberrant mesenchymal progenitor cell (MPC) osteochondral ossification, resulting in HO formation. Further, using human cells and our experimental clinically relevant murine models of HO, we have identified that interferon-beta (IFNβ), via a janus kinase (JAK) / signal transducer and activator of transcription (STAT) mechanism induces JMJD3 in Mφs. These results have led to our central hypothesis that IFNꞵ/JAK/STAT3 signaling directly increases Jmjd3 expression in HO tissue macrophages and that JMDJ3 increases macrophage Tgfb1 expression thus promoting aberrant MPC fate and HO formation. We further postulate that Mφ specific repression of JAK1/3 or JMJD3 and thus, TGFꞵ1 production using a novel targeted nanotherapy will halt HO formation and progression. As such, we propose the following aims: Aim 1: Elucidate the IFNꞵ1/JAK1/STAT3- mediated mechanism that regulates Mφ-specific JMJD3 expression in human and mouse HO wounds. Aim 2: Define the regulation of wound Mφ JMJD3 on TGFꞵ1 expression and the paracrine effects of Mφ JMJD3 on MPC fate under conditions of normal and aberrant wound healing (HO) in vivo. Aim 3: Examine the Mφ specificity and therapeutic efficacy and timing of Mφ-targeted JMJD3 and JAK1/3 nanoparticles on MPC phenotype and HO formation. In this translational project, our data will pave the way for the development of promising preventive nanotherapeutic agents aimed at cell-specific targeting of epigenetic enzymes that mediate Mφ regulation of MPC fate and thereby prevent HO development following injury.


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 = $554,064 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/6/2026	NON-COMPETING CONTINUATION	$554,064
														Subtotal = $554,064

Issue Date FY: 2025 ( Subtotal = $597,156 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/11/2025	NON-COMPETING CONTINUATION	$43,092
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/17/2024	NON-COMPETING CONTINUATION	$554,064
														Subtotal = $597,156

Issue Date FY: 2024 ( Subtotal = $597,156 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/3/2024	NON-COMPETING CONTINUATION	$43,092
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/16/2024	NON-COMPETING CONTINUATION	$554,064
														Subtotal = $597,156

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $609,471 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/27/2022	NON-COMPETING CONTINUATION	$609,471
														Subtotal = $609,471

Issue Date FY: 2021 ( Subtotal = $643,472 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/30/2021	NEW	$643,472
														Subtotal = $643,472

Grand Total All Awards = $3,001,319

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Targeting jmjd3 mitigates heterotopic ossification

Award Number: R01AR079863

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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