The mandibular condylar cartilage plays a central role in craniofacial disorders, such as mandibular growth abnormalities (micrognathia or prognathia) and temporomandibular joint (TMJ) degeneration, which afflict over 50 million Americans. The mandibular condylar cartilage differs from other articular cartilages in that it undergoes endochondral ossification and robustly remodels, during growth, to mechanical loading cues. However, similar to other joints, the TMJ degenerates with age. Women between the ages 44-55 are the most likely to seek treatment for TMJ degenerative diseases, suggesting a role of estrogen in the disease process. In long bones, estrogen receptor (ER) signaling has been extensively studied and characterized in mediating endochondral growth plate fusion. In contrast, little is known about the role of ER signaling in regulating endochondral mandibular condylar cartilage growth. Our long term goal is to determine the molecular mechanisms regulating mandibular condylar growth and differentiation. The goal of the project is to examine the role of ER alpha and ER beta. Our central hypothesis for this application is that estrogen via ER alpha and ER beta cause cessation of mandibular condylar growth, thereby accelerating age-related TMJ degeneration. To test our hypothesis, we propose the following Specific Aims:
Aim 1 - Delineate the estrogen receptor signaling pathways that regulate mandibular condylar growth- Our hypothesis for this aim is that estrogen via an ER alpha-sost pathway promotes chondrogenesis and estrogen via an ER beta-tieg1 pathway promotes proliferative pool exit causing cessation of growth. The role of ER alpha, Tieg1 and ER beta in regulating mandibular condylar cartilage growth will be evaluated by altering the estrogen levels in Tieg1 Knockout (KO), ER alpha KO, ER beta KO and Double ER alpha/beta KO mice and examining their mandibular condylar cartilage phenotype and maturation.
Aim2 - Determine the effects of estrogen signaling on progenitor cell depletion and degeneration -Our hypothesis for this aim is that estrogen via ER alpha and ER beta promote progenitor cell depletion, thereby inhibiting mechanical loading induced TMJ remodeling and accelerating age related TMJ degeneration. In order to examine this mandibular condylar cartilage cell differentiation potential, the anabolic response to mechanical loading induced remodeling and TMJ degeneration in adult and elderly ER alpha KO, ER beta KO and ER alpha/beta DKO mice will be evaluated. We believe that our proposed experiments will help reveal why temporomandibular joint degeneration predominantly afflicts women between the ages of 44-55, and also lead to new approaches to treat mandibular condylar growth abnormalities.

Public Health Relevance

Approximately, 10% of the United Sates population has suffered from temporomandibular joint disorders (TMD). TMD predominantly affects women, but the reasons behind this are unknown. This proposal examines the mechanism behind estrogen inhibition of growth and differentiation of the mandibular condylar cartilage, which will give further insight into the age and gender predilection of TMD.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
High Priority, Short Term Project Award (R56)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Lumelsky, Nadya L
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Columbia University (N.Y.)
Schools of Dentistry
New York
United States
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Robinson, Jennifer L; Soria, Paola; Xu, Manshan et al. (2018) Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Degeneration via Estrogen Receptor Alpha in Female Mice. Sci Rep 8:8527
Robinson, J L; Gupta, V; Soria, P et al. (2017) Estrogen receptor alpha mediates mandibular condylar cartilage growth in male mice. Orthod Craniofac Res 20 Suppl 1:167-171
Robinson, J L; Cass, K; Aronson, R et al. (2017) Sex differences in the estrogen-dependent regulation of temporomandibular joint remodeling in altered loading. Osteoarthritis Cartilage 25:533-543
Robinson, Jennifer; O'Brien, Alina; Chen, Jing et al. (2015) Progenitor Cells of the Mandibular Condylar Cartilage. Curr Mol Biol Rep 1:110-114
Polur, Ilona; Kamiya, Yosuke; Xu, Manshan et al. (2015) Oestrogen receptor beta mediates decreased occlusal loading induced inhibition of chondrocyte maturation in female mice. Arch Oral Biol 60:818-24
Chen, J; Kamiya, Y; Polur, I et al. (2014) Estrogen via estrogen receptor beta partially inhibits mandibular condylar cartilage growth. Osteoarthritis Cartilage 22:1861-8
Kamiya, Yosuke; Chen, Jing; Xu, Manshan et al. (2013) Increased mandibular condylar growth in mice with estrogen receptor beta deficiency. J Bone Miner Res 28:1127-34