Estrogen Receptor Beta Regulation of Mandibular Condylar Growth

描述（由申请人提供）：我们研究的长期目标是了解调节下颌髁突软骨生长和分化的机制。下颌髁突软骨来源于骨膜，由4个区带组成，其中含有处于软骨内骨化不同阶段的细胞。下颌髁突软骨通过调节软骨发生和软骨内骨化来响应外部机械应变进行重塑，以实现机械应力和关节承载能力之间的更好平衡。雌激素调节髁突软骨生长和分化。已知雌激素介导的对机械负荷诱导的骨膜骨形成和轴向骨骼生长的抑制需要雌激素受体β（ER）。然而，雌激素在下颌髁突软骨中的调节作用的机制仍不清楚。本申请的总体目标是检查雌激素状态对机械负荷诱导的下颌髁突软骨生长的调节的影响。我们的中心假设是雌激素通过ER <$抑制雌性小鼠下颌髁突软骨中的软骨细胞成熟，因此会影响髁突软骨对机械应力的反应。为了检验这一假设，将检查以下特定目的：特定目的1：检查ER缺陷小鼠的下颌髁突生长。将评估雄性和雌性野生型（WT）和ER 2缺陷小鼠中的基底下颌髁突软骨生长和分化。此外，将在用或不用雌激素处理的假手术或卵巢切除WT和ER缺陷小鼠中检查下颌髁状突生长。具体目标2：在TMJ负荷模型中检查ER <$在下颌髁突软骨分化调节中的作用。将两种导致下颌骨软骨细胞分化增加或减少的体内TMJ机械负荷模型应用于雄性和雌性WT和ER？缺陷小鼠。将从两种模型中评估下颌髁突生长和分化。更多地了解如何下颌髁突软骨重塑是由雌激素和机械负荷控制，将有助于了解颞下颌关节（TMD）的疾病，这有一个好发于18岁至45岁的女性，也可能导致新的方法来关节再生。 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，但其背后的原因尚不清楚。本研究旨在探讨雌激素抑制髁突软骨生长和分化的机制，为进一步了解TMD的年龄和性别易感性提供依据。

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.