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Coupling energy availability to ECM synthesis in chondrocytes.

Award Number: R21AR088461
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: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Coupling energy availability to ECM synthesis in chondrocytes. - ABSTRACT During the postnatal period of long bone growth, chondrocytes must balance intense extracellular- matrix (ECM) production with proteostasis under hypoxia, hyperosmolarity and low nutrients conditions in the avascular growth plate. Understanding how chondrocytes achieve this balance, and the underlying mechanisms can provide new opportunities to manipulate chondrocyte biology in health and disease. The transcription factor TonEBP/Nfat5 is best known for its role in osmotic cell response. It exists as two main isoforms in mouse and human chondrocytes (A and B). We obtained new genetic evidence that TonEBP is necessary, in a chondrocyte-intrinsic and time- sensitive manner, for normal bone growth and to maintain the balance between anabolic and catabolic processes. Our preliminary data identified a sharp surge in translational demand at the weaning period in mice, during which mTORC1 becomes overactive in prehypertrophic chondrocytes lacking TonEBP. This increase in mTORC1 activity was associated with impaired autophagy, increase of protein translation, enlarged hypertrophic lacunae and column disorganization. We also found that TonEBP Isoform A expression increases under nutrient stress and forms cytoplasmic puncta. These new findings depart from the canonical knowledge of TonEBP as a transcription factor and suggest a non-nuclear role of this TonEBP isoform in the chondrocyte cytoplasm at the lysosome–autophagy interface. Our hypothesis is that TonEBP, through its isoform A, functions as a brake on mTORC1 activation at time of rapid bone growth to maintain chondrocyte proteostasis, ECM output and allow efficient bone elongation. The first aim of this application is to determine if overactivation of mTORC1 is the cause of the defect of autophagy and growth plate organization observed in cKO mice lacking TonEBP in Col2+ chondrocytes, using genetic and pharmacologic mTORC1 inhibition. The second aim of this proposal is to determine if and how the cytoplasmic isoform A of TonEBP tunes mTORC1– autophagy coupling and matches protein production with energy availability, using isoform cellular tracing and interactome analyses. This work will clarify how the alternative splicing of TonEBP contributes to the control of the anabolic output of chondrocytes during the phase of rapid bone growth, and provide new additional points of control to manipulate the behavior of chondrocytes for therapeutic or bioengineering purposes.


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: 2026 ( Subtotal = $374,000 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	8/21/2026	NEW	$0
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/19/2026	NEW	$374,000
														Subtotal = $374,000

Grand Total All Awards = $374,000

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Coupling energy availability to ECM synthesis in chondrocytes.

Award Number: R21AR088461

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: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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