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Chondrocyte-derived bone cells determine the overall pattern of TMJ condyle and contribute to bone remodeling

Award Number: R01DE025659
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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TMD (Temporomandibular joint disorders) affect 5-10% of the population in this country, with severe TMD requiring surgical repair. The cause for TMD is often hard to determine, and the pathophysiology underlying this affliction remains unclear, as the mandibular condylar cartilage (MCC) differs considerably in its development and structure from both a growth plate or an articular cartilage. However, the regulation of TMJ development and growth has been under-studied. Chondrogenesis in the TMJ or limbs has been considered a linked but separate process from osteogenesis during endochondral bone formation. How can the inherited message be transmitted from chondrocytes, which supposedly undergo cell death before bone formation, to the cells that form bone? The answer to this question may lie in recent studies indicating that a direct transformation of chondrocytes to osteoblasts occurs. Yet, the following key questions remain: how is this cell transformation linked to bone growth and remodeling? What is the underlying molecular mechanism? Which genes are required for cell transformation? We propose that chondrogenesis and osteogenesis are one continuous process in which chondrocyte-derived bone cells (CBC) define the overall pattern of MCC-ramus and contribute to bone remodeling via Bmpr1a (BMP receptor 1a, a key receptor for BMP2 and BMP4) and ¿-catenin. This hypothesis is based on: 1) Published data from our lab and others demonstrating that direct cell transformation occurs in MCC and limbs; 2) Deleting Bmpr1a or ¿-catenin in chondrocytes leads to drastic changes in the condyle and limbs during growth and bone remodeling, though deletion of either gene in bone cells has little impact on the skeletal pattern; and 3) The molecular regulation of cell transformation is highly dependent on the skeletal elements, developmental stage, and different genes. We will test this hypothesis using the following highly related but independent Aims: 1) To determine molecular regulation of cell transformation by Bmpr1a during growth and bone remodeling. Working hypothesis: the CBC defines the overall morphology of the condyle and limbs via BMPR1A that plays variant roles in different elements of the skeleton; and 2): To determine molecular regulation of cell transformation by ¿-catenin during growth and bone remodeling. Working hypothesis: ¿-catenin plays variant roles in the condyle vs. limbs in defining skeletal pattern and bone remodeling in a manner that differs from Bmpr1a; and 3): To determine how chondrocytes demineralize cartilage matrices and form bone cells ex vivo, and shift expression profiles of genes directly linked to bone cells in vitro. Working hypothesis: HCs, which migrate, play a dual role in removing calcified cartilage and cell transformation. We expect that CBC is responsible for most endochondral bone formation and remodeling, regulated by Bmpr1a and ¿-catenin. We predict that this phenomenon also occurs in limbs, although differentially regulated by these genes. Finishing this project will likely revise the current dogma, provide new knowledge in this understudied area, and form a basis for developing novel approaches to prevent, diagnose, and treat TMD, as well as other skeletal diseases.


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 = -$91,573 )
2023	2021	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Oral Diseases and Disorders Research	000	5	9/7/2023	NON-COMPETING CONTINUATION	-$91,573
														Subtotal = -$91,573

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	5	5/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $352,688 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	001	5	2/19/2021	NON-COMPETING CONTINUATION	$35,269
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	5	12/7/2020	NON-COMPETING CONTINUATION	$317,419
														Subtotal = $352,688

Issue Date FY: 2020 ( Subtotal = $352,688 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	000	4	11/20/2019	NON-COMPETING CONTINUATION	$317,419
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Oral Diseases and Disorders Research	001	4	2/18/2020	NON-COMPETING CONTINUATION	$35,269
														Subtotal = $352,688

Issue Date FY: 2019 ( Subtotal = $352,688 )
2019	2019	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	000	3	12/21/2018	NON-COMPETING CONTINUATION	$352,688
														Subtotal = $352,688

Issue Date FY: 2018 ( Subtotal = $352,688 )
2018	2018	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	001	2	4/19/2018	NON-COMPETING CONTINUATION	$35,269
2018	2018	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	000	2	12/7/2017	NON-COMPETING CONTINUATION	$317,419
														Subtotal = $352,688

Issue Date FY: 2017 ( Subtotal = $352,688 )
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	001	1	2/28/2017	NEW	-$18,562
2017	2017	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Oral Diseases and Disorders Research	000	1	12/9/2016	NEW	$371,250
														Subtotal = $352,688

Grand Total All Awards = $1,671,867

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Chondrocyte-derived bone cells determine the overall pattern of TMJ condyle and contribute to bone remodeling

Award Number: R01DE025659

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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