Estrogen Receptor Beta Regulation of Mandibular Condylar Growth

描述（申请人提供）：我们的长期研究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个区组成，其中包含软骨内成骨不同阶段的细胞。下颌髁突软骨通过调节软骨形成和软骨内成骨来应对外部机械应变，从而更好地平衡关节的机械应力和承载能力。雌激素调节下颌髁软骨的生长和分化。众所周知，雌激素介导的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，雌激素对下颌髁软骨调节作用的机制尚不清楚。本应用程序的总体目的是检查雌激素状态对机械载荷诱导的下颌髁软骨生长的调节作用。我们的中心假设是雌激素通过雌激素受体抑制雌性小鼠下颌髁突软骨的软骨细胞成熟，从而影响髁突软骨对机械应力的反应。为了验证这一假设，将检查以下具体目标；特异性目的1：研究ER¿缺乏小鼠的下颌髁生长。将评估雄性和雌性野生型（WT）和ER2缺陷小鼠的基底下颌髁软骨生长和分化。此外，将在假手术或去卵巢的WT和ER¿缺陷小鼠中，用雌激素或不雌激素治疗，检查下颌髁的生长情况。具体目的2：探讨ER¿在TMJ负荷模型中调节下颌髁突软骨分化的作用。将两种导致下颌软骨细胞分化增加或减少的TMJ机械负荷模型应用于雄性和雌性WT和ER¿缺陷小鼠。下颌髁的生长和分化将从两种模型中进行评估。更好地了解下颌骨髁突软骨重塑是如何受雌激素和机械负荷控制的，将有助于理解颞下颌双关节（TMD）疾病，这些疾病主要发生在18至45岁的女性之间，也可能导致关节再生的新方法。

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.