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Growth hormone regulating chondrocyte metabolism for osteoarthritis development

Award Number: R01AR081804
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: 07/03/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Growth hormone regulating chondrocyte metabolism for osteoarthritis development - Project Summary Most older adults (~60 years of age) have some signs of osteoarthritis (OA) in their joints. Unfortunately, there are no disease-modifying therapies for OA due to our lack of insight into the underlying pathophysiology. GH is an FDA approved drug to treat certain diseases such as growth hormone deficiency (GHD). Additionally, GH secretion decreases over time, causing some older adults to consider the use of GH replacement as a means to counteract aging related conditions. However, over-production or prolonged usage of GH has been reported to have many side effects including joint degeneration and joint pain. Identifying the mechanisms by which GH causes joint cell dysfunction during aging could inform effective interventions and therapeutic strategies that reduce the incidence and impact of OA. Our preliminary studies have shown that over-expression of GH gene in mice predispose mice into progressive joint degeneration, while blocking GH action through systemic GH receptor disruption protect mice from developing OA. We showed that GH robustly altered the metabolism of cells (i.e, chondrocytes) in cartilage. Yet, it is still unknown if blocking GH’s action specifically on cartilage tissue would be protective. Guided by our preliminary data and the literature, we will investigate this question via three specific aims: Aim 1. Determine how blocking GH action on cartilage through cartilage specific deletion of GHR affects OA development; Aim 2. Determine the mechanisms by which GH promotes chondrocyte hypertrophic changes and OA development. Aim 3. Determine if GH receptor antagonism (GHa) protects mice from developing OA. Well-established mouse models GH over-expression and GH receptor tissue specific deletion will be used to examine the consequences of enhancing or inhibiting GH action in cartilage on OA pathology. In vivo and in vitro metabolic profiling methods will be leveraged to determine the effects of manipulating GH signaling on chondrocyte cellular metabolism. Last but not least, a unique mouse model that was used for discovery of Pegvisomant, an FDA approved drug for treating acromegaly, will be used to test if blocking GH is beneficial for joint health. Successful completion of this research is expected to provide more comprehensive understanding of how GH affects joint cell functions, offering the potential to provide new therapeutic targets for OA treatment.


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: 2025 ( Subtotal = $473,983 )
2025	2025	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/15/2025	NON-COMPETING CONTINUATION	$473,983
														Subtotal = $473,983

Issue Date FY: 2024 ( Subtotal = $510,843 )
2024	2024	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/23/2024	NON-COMPETING CONTINUATION	$510,843
														Subtotal = $510,843

Issue Date FY: 2023 ( Subtotal = $501,950 )
2023	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/3/2023	NEW	$501,950
														Subtotal = $501,950

Grand Total All Awards = $1,486,776

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Growth hormone regulating chondrocyte metabolism for osteoarthritis development

Award Number: R01AR081804

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: 07/03/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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