Thursday, April 25, 2024 4/25/2024

Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage

Award Number: R01AG058624
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

ABSTRACT The reparative capacity in human articular cartilage is generally considered to be low or negligible, and this intrinsic capacity decreases with age. As a result, articular cartilage injuries often result in irreversible damage leading to osteoarthritis (OA). We and others have recently defined heterogeneity in articular chondrocytes at both the molecular and cellular levels. Work in mice and other mammals has implicated a subset of cells in the superficial layer of articular cartilage as the source of regenerative capacity; to date, these findings have not been extended to a specific population of chondrocytes in human ontogeny. Our previous studies have shown that unlike adult chondrocytes, fetal chondrocytes are highly proliferative and migratory, and exhibit high basal levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Our preliminary data also nominate cells expressing integrin a4 (ITGA4) and bone morphogenetic protein receptor (BMPR1B) as the most immature chondrocytes in human articular cartilage throughout human development. Moreover, we have shown at the molecular level that ITGA4+BMPR1B+ cells are enriched for active STAT3 (pSTAT3), which are known to drive proliferation, anabolism and preserve differentiation potential. Importantly, adult ITGA4+BMPR1B+ cells are localized to the superficial layer and also express the highest levels of SOX9, which is strongly identified with osteochondral progenitor identity and anabolism; indeed, ITGA4+BMPR1B+ cells are robustly chondro- and osteogenic in vitro. The percentage of ITGA4+BMPR1B+ cells and levels of pSTAT3 tightly correlate with biological age, decreasing from 20-30% in developing joints down to 1-2% in aged adult healthy cartilage. We hypothesize that active STAT3 is expressed in immature articular chondrocytes and is a permissive factor required for immature cell anabolism and differentiation in response to specific instructive signals in the niche. We propose to define the direct transcriptional targets of STAT3 in human articular chondrocytes at different ontogenic stages and under conditions similar to the pro-inflammatory state driven by IL-6 family cytokines in OA. To address how IL-6 family cytokines can drive varied biological and functional outcomes in a context- specific manner, we will employ nanoproteomics and targeted mutagenesis to determine how specific post- translational modifications in the core IL-6 family cytokine receptor gp130 differ in fetal vs. adult chondrocytes stimulated with IL-6 family cytokines. Finally, we will apply single cell RNA-Seq to further refine the molecular and cellular phenotype of immature articular chondrocytes. In parallel, we will assess the molecular and functional consequences of STAT3 gain and loss of function in articular chondrocytes. We propose that cells with higher levels of pSTAT3 will evidence broader differentiation potential in vivo, resulting from changes mediated by STAT3 in chromatin conformation. The overall impact of this highly innovative study is to define the cellular and molecular phenotype of immature articular chondrocytes throughout human ontogeny and to link this to the potential for cartilage repair and/or regeneration during aging.


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: 2023 ( Subtotal = $338,250 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	5	1/19/2023	NON-COMPETING CONTINUATION	$338,250
														Subtotal = $338,250

Issue Date FY: 2022 ( Subtotal = $338,250 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	4	12/16/2021	NON-COMPETING CONTINUATION	$304,425
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	001	4	4/21/2022	NON-COMPETING CONTINUATION	$33,825
														Subtotal = $338,250

Issue Date FY: 2021 ( Subtotal = $338,250 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	3	12/16/2020	NON-COMPETING CONTINUATION	$304,425
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	001	3	2/11/2021	NON-COMPETING CONTINUATION	$33,825
														Subtotal = $338,250

Issue Date FY: 2020 ( Subtotal = $338,250 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	001	2	1/17/2020	NON-COMPETING CONTINUATION	$33,825
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	2	11/26/2019	NON-COMPETING CONTINUATION	$304,425
														Subtotal = $338,250

Issue Date FY: 2019 ( Subtotal = $363,000 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	001	1	8/10/2019	NEW	$24,750
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	1	1/14/2019	NEW	$338,250
														Subtotal = $363,000

Grand Total All Awards = $1,716,000

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage

Award Number: R01AG058624

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer