CATHEPSIN EXPRESSION IN OSTEOCLASTS DURING AGING

破骨细胞产生大量的半胱氨酸蛋白酶和组织蛋白 B，L和K.骨吸收依赖于骨组织的降解 由组织蛋白酶分泌到附件中的细胞外基质 破骨细胞和骨表面之间的区域。甲状旁腺激素和 降钙素分别诱导和抑制组织蛋白酶L的分泌和 骨骼中的活动。维甲酸和雌激素刺激和抑制， 组织蛋白酶K在破骨细胞中的表达。因此， 组织蛋白酶在骨吸收中起主要作用，其表达可能 由已知的调节骨吸收的因素调节。骨质疏松 以总骨量和骨量的进行性丢失为特征 密度。I型骨质疏松症(围绝经期)依赖激素， 但II型骨质疏松症(老年性)在男性和女性中都会发生，而且 与年龄有关的。因为许多正常的和病理的影响 组织蛋白酶与它们的合成水平、组织蛋白酶的程度有关 表达可能在骨质疏松症的发病机制中起重要作用 是这个国家发病率的主要原因之一，导致 每年超过一百万的骨折和增加的死亡率 髋部骨折。 我们假设衰老调节荷尔蒙和 细胞因子通过改变组织蛋白酶的表达影响骨吸收 通过破骨细胞。为了验证这一假设，我们希望执行以下操作 实验：特定目标1.确定活性物质是否存在于骨骼中 生理调节破骨细胞中组织蛋白的表达。特定的 目的2.确定破骨细胞组织蛋白酶的表达是否随 年龄。具体目标3.确定组织蛋白酶的表达是否与 与骨吸收的程度有关。 从这些初步研究中获得的数据将构成以下方面的基础 未来研究的信号转导途径导致 组织蛋白酶基因的表达。最终，这将允许我们开发 将调节破骨细胞来源的组织蛋白酶的治疗策略 活动和预防伴随骨质疏松而来的破坏性事件。

Osteoclasts produce large amounts of the cysteine proteinases cathepsins B, L, and K. Bone resorption depends upon the degradation of the extracellular matrix by cathepsins that are excreted into the attachment zone between osteoclasts and the bone surface. Parathyroid hormone and calcitonin, respectively, induce and suppress cathepsin L secretion and activity in bone. Retinoic acid and estrogen stimulate and inhibit, respectively, cathepsin K expression in osteoclasts. Therefore, cathepsins play a major role in bone resorption, and their expression may be regulated by factors known to modulate bone resorption. Osteoporosis is characterized by a progressive loss of total bone mass and bone density. Type I osteoporosis (peri-menopausal) is hormonally dependent, but type II osteoporosis (senile) occurs in both males and females and is aged-related. Since many of the normal and pathological effects of cathepsin relate to their levels of synthesis, the degree of cathepsin expression could be important in the pathogenesis of osteoporosis, which is one of the leading causes of morbidity in this country, resulting in over one million fractures each year and increased mortality for those with hip fractures. We hypothesize that aging modulates the effects that hormones and cytokines exert upon bone resorption via changes in cathepsin expression by osteoclasts. To test this hypothesis, we wish to perform the following experiments: Specific Aim 1. Determine whether agents active in bone physiology regulate the expression of cathepsins in osteoclasts. Specific Aim 2. Determine whether cathepsin expression by osteoclasts changes with age. Specific Aim 3. Determine whether cathepsin expression correlates with the extent of bone resorption. The data obtained from such pilot studies will form the foundation for future investigation of the signal transduction pathways leading to cathepsin gene expression. Ultimately this could permit us to develop therapeutic strategies that will modulate osteoclast-derived cathepsin activity and prevent the destructive events that accompany osteoporosis.