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Cellular and molecular mechanisms regulating synovial joint development

Award Number: K01AR078387
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Cellular and molecular mechanisms regulating synovial joint development - Project Summary and Abstract Synovial joints are essential for body motion and quality of life. Their synovial cavity and lubricant-rich fluid permit unhindered joint motion and function and provide tissue protection and nourishment. While these aspects of synovial joint biology are well understood, little is known about how the cavity and its fluid actually develop during embryogenesis. At early fetal stages, the limb skeletal primordia are composed of continuous cartilaginous structures without joints. Joint development starts with appearance of an “interzone”, a tissue made of mesenchymal cells expressing the growth and differentiation factor 5 gene (Gdf5). We previously showed that Gdf5+ cell progenies produce most joint tissues over time and the synovial cavity forms in the middle of the interzone. Because the interzone cells are initially attached to each other, the cavitation process must involve their physical separation along the prospective articular line to facilitate the creation of a fluid-filled cavity. Previous studies indicated that interzone cells produce hyaluronan (HA) around the cavitation time, and this is accompanied by accumulation of a HA-rich matrix in local tissues. HA is a major component of extracellular matrix and synovial fluid and plays important roles in tissue homeostasis. In my preliminary studies, I found that just before cavitation onset, interzone cells in mouse embryo limbs express hyaluronan synthase 2 (HAS2, ‘the HA synthesizer’) and transmembrane protein 2 (TMEM2), a cell surface hyaluronidase that specifically cleaves high molecular weight HA into intermediate and biologically-active fragments. I also discovered that, morphologically, cavitation initiates with formation of microlumens along the prospective articular line and is completed soon afterwards when the pockets coalesce to generate a single one synovial cavity. This process is extremely rapid in the developing knee but is slower in digits. These and other novel data lead to my central hypothesis that joint cavitation is brought about by convergence of diverse but coordinated biological processes. Accordingly, Aim 1 is to determine the role of HAS2 and TMEM2 in joint cavitation using genetically modified mouse models. I will conditionally delete Has2 and/or Tmem2 in interzone cells (using Gdf5Cre mice) and subject resulting mutant embryos to detailed analysis. Aim 2 is to determine cellular and molecular mechanisms of cavitation. I will investigate downstream signaling pathways in response to changes in HA sizes and resulting interactions with cell surface CD44 receptor, regulating HA metabolism in synovial joint development and long-term maintenance. The project will provide novel insights into mechanisms underlying joint development and cavitation. In line with the K01 mechanism, the project will allow me to acquire new expertise in skeletal developmental and molecular biology and to integrate it with my previous training in bioengineering. This unique combination of expertise in two distinct but interrelated fields will allow me to establish an independent career distinct from my mentors and create novel therapeutic tools to repair and regenerate cartilage for the treatment of joint conditions such as osteoarthritis (OA).


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 = $73,176 )
2025	2025	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/24/2025	NON-COMPETING CONTINUATION	$73,176
														Subtotal = $73,176

Issue Date FY: 2024 ( Subtotal = $73,176 )
2024	2024	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	4	8/27/2024	NON-COMPETING CONTINUATION	$73,176
2024	2023	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	1/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$17,208
2024	2023	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	3/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	-$17,208
														Subtotal = $73,176

Issue Date FY: 2023 ( Subtotal = $73,176 )
2023	2023	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	8/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$73,176
2023	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	9/6/2023	NON-COMPETING CONTINUATION	$0
2023	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $73,176

Issue Date FY: 2022 ( Subtotal = $73,176 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/21/2022	NON-COMPETING CONTINUATION	$73,176
														Subtotal = $73,176

Issue Date FY: 2021 ( Subtotal = $73,176 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/20/2021	NEW	$73,176
														Subtotal = $73,176

Grand Total All Awards = $365,880

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Cellular and molecular mechanisms regulating synovial joint development

Award Number: K01AR078387

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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