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OA Pathogenesis beyond Cartilage: A preclinical study of the sources of OA pain

Award Number: R01AR071431
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: 03/01/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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OA Pathogenesis beyond Cartilage: A preclinical study of the sources of OA pain - Project Summary A 2010 public awareness campaign entitled “Fight Arthritis Pain” promoted moving is the best medicine! While clinical studies overwhelmingly confirm exercise is an effective osteoarthritis (OA) treatment, patients often find this advice counterintuitive - “The solution for a painful joint is to use it more?” Part of this confusion is driven by chondrocentric definitions of OA, which imply that more cartilage damage will lead to more pain. However, OA is a `disease of the joint as an organ' with changes occurring throughout the joint. Moreover, factors that affect OA pain and disability occur both within and beyond the articular joint, including changes in joint structure, inflammation, and neuroplasticity. Understanding how these complex factors contribute to the patients' primary concerns - pain and disability - can help identify critical targets for OA therapy. Preclinical OA models should be a powerful tool to help researchers identify physiologic links between OA pathogenesis and symptomology, offering an opportunity to investigate facets of OA that cannot be easily explored in humans. Toward this goal, this proposal will use novel rodent gait analyses and measures of hind limb sensitivity to investigate how changes in joint structure, intra-articular inflammation, and dorsal root ganglia neuroplasticity relate to the development of OA-related pain and disability in rat models of post-traumatic knee OA. First, 3D measures of bony structures will be acquired in our models using a nanoCT, and 3D changes in cartilage and synovium will be assessed using selective plane illumination microscopy (SPIM) on optically- cleared knees (Aim 1). This aim will allow us to investigate relationships between complex 3D joint structures and OA-related pain and disability. Second, the missing link between OA pathogenesis and OA pain is often assumed to be inflammation, which can temporally cycle without major shifts in joint structure. In this proposal, intra-articular inflammation will be directly examined in our models; moreover, the distribution and quantity of macrophages will be examined using SPIM on optically cleared knees (Aim 2). Third, chronic exposure to low grade inflammation can lower the threshold of dorsal root ganglia (DRG) neurons. In this proposal, patch clamp recordings will be used to investigate DRG sensitization subsequent to simulated joint injuries (Aim 3). Additionally, all studies will be collected in the context of OA-related pain and disability, using mechanical hypersensitivity testing and gait analysis to quantify OA-related symptoms in the rat. Finally, a well-established and effective OA therapy - moderate exercise - will be evaluated in each aim to discern how exercise modifies the physiology of the OA-affected knee and leads to improvement in OA-related symptoms. Overall, this approach will use innovative, quantitative methods to simultaneously study joint structure, inflammation, and neuroplasticity in a manner that is not possible in humans, allowing us to assess how these mechanisms contribute to the continuum of OA pain and disability.


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 = -$11,143 )
2025	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/7/2025	NON-COMPETING CONTINUATION	-$8,887
2025	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	1/7/2025	SUPPLEMENT FOR EXPANSION	-$2,256
														Subtotal = -$11,143

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $379,032 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/7/2022	NON-COMPETING CONTINUATION	$302,308
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	3/9/2022	SUPPLEMENT FOR EXPANSION	$76,724
														Subtotal = $379,032

Issue Date FY: 2021 ( Subtotal = $751,674 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/3/2021	SUPPLEMENT FOR EXPANSION	$76,724
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/30/2021	NON-COMPETING CONTINUATION	$350,951
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	5/12/2021	SUPPLEMENT FOR EXPANSION	$323,999
														Subtotal = $751,674

Issue Date FY: 2020 ( Subtotal = $426,425 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	8/15/2020	SUPPLEMENT FOR EXPANSION	$38,363
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/28/2020	NON-COMPETING CONTINUATION	$349,256
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/5/2020	NON-COMPETING CONTINUATION	$38,806
														Subtotal = $426,425

Issue Date FY: 2019 ( Subtotal = $380,017 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/7/2019	NON-COMPETING CONTINUATION	$380,017
														Subtotal = $380,017

Issue Date FY: 2018 ( Subtotal = $346,383 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/26/2018	NEW	$346,383
														Subtotal = $346,383

Grand Total All Awards = $2,272,388

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OA Pathogenesis beyond Cartilage: A preclinical study of the sources of OA pain

Award Number: R01AR071431

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: 03/01/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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