Estrogen Receptor Beta Regulation of Mandibular Condylar Growth

描述(申请人提供)：我们研究的长期目标是了解调控下颌骨髁状突软骨生长和分化的机制。下颌骨髁状突软骨来源于骨膜，由4个区域组成，包含软骨内骨化不同阶段的细胞。下颌骨髁状突软骨通过调节软骨生成和软骨内成骨来响应外界的机械应变而重塑，从而在机械应力和关节承载能力之间达到更好的平衡。雌激素对下颌骨髁突软骨生长和分化的调节作用众所周知，雌激素介导的抑制机械负荷诱导的骨膜成骨和轴向骨骼生长需要雌激素受体β(ER？)。然而，雌激素对下颌骨髁状突软骨的调节作用机制尚不清楚。这项应用的总体目标是检查雌激素状态对机械负荷诱导的下颌骨髁状突软骨生长的调节作用。我们的中心假设是雌激素通过内质网抑制雌性小鼠下颌骨髁突软骨细胞的成熟，从而影响髁突软骨对机械应力的反应。为了验证这一假设，将检验以下特定目标：特定目标1：检查ER缺陷小鼠的下颌骨髁状突生长。将评估雄性和雌性野生型(WT)和ER2缺陷小鼠的下颌骨髁状突软骨的生长和分化。此外，还将观察用或不用雌激素治疗WT和ER缺陷的假手术或去卵巢小鼠下颌骨的生长情况。具体目的2：探讨内质网在TMJ负荷模型中对下颌骨软骨分化的调节作用。两种导致下颌软骨细胞分化增加或减少的体内TMJ机械负荷模型将应用于WT和ER缺乏的雄性和雌性小鼠。下颌骨的生长和分化将通过这两种模型进行评估。进一步了解雌激素和机械负荷是如何控制下颌骨髁状突软骨重塑的，将有助于理解18-45岁女性好发的TMD疾病，也可能导致新的关节再生方法。 公共卫生相关性：大约10%的美国人口患有颞下颌关节紊乱病(TMD)。TMD主要影响育龄妇女，但背后的原因尚不清楚。本研究旨在探讨雌激素抑制下颌骨髁状突软骨生长和分化的机制，为进一步研究TMD的年龄和性别偏好提供依据。

DESCRIPTION (provided by applicant): The long-term goal of our research is to understand the mechanisms regulating growth and differentiation of mandibular condylar cartilage. The mandibular condylar cartilage is derived from periosteum and comprised of 4 zones that contain cells at various stages of endochondral ossification. The mandibular condylar cartilage remodels in response to external mechanical strains by regulating chondrogenesis and endochondral ossification, in order to achieve a better balance between mechanical stress and the load bearing capacity of the joint. Estrogen regulates mandibular condylar cartilage growth and differentiation. It is known that the estrogen-mediated inhibition of mechanical loading-induced periosteal bone formation and axial skeletal growth requires estrogen receptor beta (ER¿). However, the mechanisms underlying the regulatory effects of estrogen in the mandibular condylar cartilage remain unknown. The general objective of this application is to examine the effects of estrogen status on the regulation of mandibular condylar cartilage growth induced by mechanical loading. Our central hypothesis is that estrogen acts through ER¿ to inhibit chondrocyte maturation in the mandibular condylar cartilage in female mice and will, therefore, affect the response of condylar cartilage to mechanical stress. To test this hypothesis, the following Specific Aims will be examined; Specific Aim 1: Examine mandibular condylar growth in ER¿ deficient mice. Basal Mandibular condylar cartilage growth and differentiation in male and female wild type (WT) and ER2 deficient mice will be assessed. In addition, mandibular condylar growth will be examined in sham or ovariectomized WT and ER¿ deficient mice treated with or without estrogen. Specific Aim 2: Examine the role of ER¿ in the regulation of mandibular condylar cartilage differentiation in TMJ loading models. Two in vivo TMJ mechanical loading models, which cause either an increase or a decrease in mandibular chondrocyte differentiation, will be applied to male and female WT and ER¿ deficient mice. Mandibular condylar growth and differentiation will be assessed from both models. Greater understanding on how mandibular condylar cartilage remodeling is controlled by estrogen and mechanical loading will aid in the understanding of diseases of the temporomandiblar joint (TMD), which have a predilection for women between the ages of 18 and 45, and may also lead to new approaches to joint regeneration. PUBLIC HEALTH RELEVANCE: Approximately, 10% of the United Sates population has suffered from temporomandibular joint disorders (TMD). TMD predominantly affects women of childbearing ages, 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.