The overall purpose of these studies is to dissect the mechanisms by which female reproductive hormones, relaxin, estrogen, and progesterone, and their receptors contribute to the degeneration of temporomandibular joint (TMJ) fibrocartilage potentially contributing to TMJ disorders (TMJDs). The symptoms of TMJDs such as pain and limited jaw movement occur in approximately 10 million individuals in the USA. Since these disorders are highly prevalent in women of reproductive age, it has been posited that female sex hormones contribute to the initiation or progression of these disorders. In support of this concept, we have demonstrated that relaxin and / or estrogen increase and progesterone attenuates the expression of specific matrix metalloproteinase (MMP) tissue degrading enzymes and alter the matrix composition of the TMJ disc fibrocartilage. Nevertheless, several critical questions including (1) the determination of the effects of relative systemic concentrations of relaxin, estrogen and progesterone on net matrix content of TMJ tissues in vivo, and (2) the identification of MMPs and hormone receptors involved in hormone mediated joint degeneration remain unanswered. We will address these questions by testing the hypothesis that relaxin and (3-estradiol contribute to the targeted degradation of fibrocartilaginous tissues of the TMJ by activation of specific receptors to enhance the expression of key collagen- and proteoglycan-degrading MMPs, while progesterone attenuates this degradative response. Specifically, we will (1) determine the dose response effects of relaxin and progesterone in respectively enhancing and attenuating TMJ disc matrix loss in vivo, (2) use specific MMP knockout mice to identify the MMP enzymes involved in hormonally induced tissue degradation, and (3) utilize specific estrogen and relaxin receptor knockout mice to identify the receptors that contribute to joint tissue degeneration. This application addresses the primary objective of the Program Announcement namely to utilize """"""""genetically modified mouse models to explore the biological mechanisms underlying non-inflammatory joint degeneration."""""""" Identification of the MMPs and receptors involved in hormone mediated degradation of TMJ fibrocartilage will provide early and specific therapeutic targets during reversible stages of the disease process that would be important in preventing or alleviating the progression of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018455-03
Application #
7659648
Study Section
Special Emphasis Panel (ZRG1-MOSS-E (02))
Program Officer
Kusiak, John W
Project Start
2007-09-01
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$364,546
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ahmad, N; Chen, S; Wang, W et al. (2018) 17?-estradiol Induces MMP-9 and MMP-13 in TMJ Fibrochondrocytes via Estrogen Receptor ?. J Dent Res 97:1023-1030
Park, Y; Hosomichi, J; Ge, C et al. (2015) Immortalization and characterization of mouse temporomandibular joint disc cell clones with capacity for multi-lineage differentiation. Osteoarthritis Cartilage 23:1532-42
Kapila, Sunil; Park, Young; Ahmad, Nisar et al. (2013) Mechanisms for relaxin's modulation of MMPs and matrix loss in fibrocartilages. Ital J Anat Embryol 118:62-5
Ahmad, Nisar; Wang, Wei; Nair, Remi et al. (2012) Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: induction of MMP-9 involves the PI3K, ERK, Akt and PKC-? pathways. Mol Cell Endocrinol 363:46-61
Joseph, Jeena; Kapila, Yvonne L; Hayami, Takayuki et al. (2010) Disease-associated extracellular matrix suppresses osteoblastic differentiation of human periodontal ligament cells via MMP-1. Calcif Tissue Int 86:154-62
Kapila, Sunil; Wang, Wei; Uston, Karen (2009) Matrix metalloproteinase induction by relaxin causes cartilage matrix degradation in target synovial joints. Ann N Y Acad Sci 1160:322-8
Wang, W; Hayami, T; Kapila, S (2009) Female hormone receptors are differentially expressed in mouse fibrocartilages. Osteoarthritis Cartilage 17:646-54
Kapila, S; Xie, Y; Wang, W (2009) Induction of MMP-1 (collagenase-1) by relaxin in fibrocartilaginous cells requires both the AP-1 and PEA-3 promoter sites. Orthod Craniofac Res 12:178-86
Wadhwa, Sunil; Kapila, Sunil (2008) TMJ disorders: future innovations in diagnostics and therapeutics. J Dent Educ 72:930-47