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Biomechanics of Cartilage: Roles of Decorin in ECM Assembly and Degradation

Award Number: R01AR074490
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: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Biomechanics of Cartilage: Roles of Decorin in ECM Assembly and Degradation - PROJECT SUMMARY The development of novel cartilage regeneration and osteoarthritis (OA) treatments is limited by our incomplete understanding of how certain molecular activities in cartilage extracellular matrix (ECM) are linked to its matrix assembly and biomechanical functions. This project will study the activities of decorin, a small leucine rich proteoglycan (SLRP), which appears to be critical for the assembly and stability of the aggrecan network, a major constituent of cartilage ECM. The overall objective is to determine the roles of decorin in regulating the assembly of the aggrecan network in healthy and degenerative cartilage. Our central hypothesis is that decorin acts as a “physical linker” to regulate the assembly of the aggrecan network in cartilage ECM, and this role enables the establishment of the normal biomechanical function of cartilage during joint development, and delays cartilage degeneration in OA by increasing the retention of fragmented aggrecan. We will elucidate the roles of decorin in normal cartilage ECM assembly (Aim 1) and in OA-associated cartilage degradation (Aim 2), respectively. In Aim 1, we will first determine whether decorin is essential for the proper biomechanical function of normal cartilage during post-natal growth. Next, we will determine whether decorin increases the retention of aggrecan in the forming neo-matrix of chondrocytes under dynamic loading, and if decorin also regulates chondrocyte anabolic response to growth factors. In Aim 2, we will first determine whether decorin slows down cartilage degradation and OA progression using two murine OA models, including naturally occurring OA in aged mice and injury-induced post-traumatic OA in the destabilization of the medial meniscus (DMM) model. Next, we will determine if decorin increases the retention of aggrecan fragments in degenerative cartilage, and if decorin also directly impacts chondrocyte catabolism in response to inflammatory factors. A number of innovative approaches will be utilized. Using cartilage-specific decorin inducible knockout mice, we will delineate decorin activities during normal cartilage homeostasis and those during the progression of OA. Applying atomic force microscopy (AFM)-nanomechanical tests, we will quantify the mechanical changes of cartilage as a result of decorin deficiency. By combining these approaches, we will elucidate the roles of decorin in regulating the structure and function of normal cartilage, and the degradation of cartilage during OA onset and progression. Successful completion of this study will establish a new structure-mechanics principle of decorin-mediated aggrecan network assembly in the cartilage ECM. This will direct our future studies to improve cartilage regeneration and to slow down OA progression by modulating the activity and availability of native decorin, as well as the design and delivery of decorin-biomimetic synthetic molecules.


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 = $0 )
2025	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	12/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $326,990 )
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/18/2024	NON-COMPETING CONTINUATION	$23,597
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/9/2024	NON-COMPETING CONTINUATION	$303,393
														Subtotal = $326,990

Issue Date FY: 2023 ( Subtotal = $337,104 )
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	2/16/2023	NON-COMPETING CONTINUATION	$33,711
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/20/2022	NON-COMPETING CONTINUATION	$303,393
														Subtotal = $337,104

Issue Date FY: 2022 ( Subtotal = $333,733 )
2022	2022	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/25/2022	NON-COMPETING CONTINUATION	$30,340
2022	2022	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/10/2022	NON-COMPETING CONTINUATION	$303,393
														Subtotal = $333,733

Issue Date FY: 2021 ( Subtotal = $328,434 )
2021	2021	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/23/2020	NON-COMPETING CONTINUATION	$304,733
2021	2021	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/8/2021	NON-COMPETING CONTINUATION	$23,701
														Subtotal = $328,434

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/21/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $363,717 )
2019	2019	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/1/2019	NEW	$363,717
														Subtotal = $363,717

Grand Total All Awards = $1,689,978

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Biomechanics of Cartilage: Roles of Decorin in ECM Assembly and Degradation

Award Number: R01AR074490

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: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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