Differentiation and Proliferation of Human Osteoblasts

人类成骨细胞的分化和增殖

• 批准号: 6479687
• 负责人: OLIVIA M. PEREIRA-SMITH
• 金额: $ 7.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479687
• 关键词: age difference; aging; cell differentiation; cell proliferation; cell senescence; cell transplantation; clinical research; gene expression; human middle age (35-64); human old age (65+); human subject; osteoblasts; osteocalcin; osteogenesis; osteonectin; osteoporosis; transcription factor; young adult human (21-34)

Clinically important bone loss is a sum of Type I osteoporosis, Type II osteoporosis and the secondary causes. In women, maximum bone mass is attained before age 35 and evidence of trabecular bone loss is already apparent at age 40, before the onset of menopause. During the post- menopausal period, the rate of bone loss is increased (Type I) for approximately 5-10 years, and after this period, bone loss continues at a decreased rate due to Type II osteoporosis. In men, the rate of bone loss is not as rapid as that of women, it is persistent and due solely to Type II osteoporosis as well as secondary causes. Longitudinal studies of vertebral bone loss reveal relatively rapid rates of osteoporosis, approaching that seen in women. The differences between the types of osteoporosis is clear but the relative importance is less clear. If estimates are correct then 1 in every 3 women will have had a hip fracture by age ninety compared to 1 in 6 men. The mortality associated with hip fracture in men aged greater than 75 years is 30%, triple that reported for women. Therefore Type II osteoporosis is a very important public health issue, not only for the impact on the healthspan of men, but also for the additive role it plays in women as well. In this condition of bone loss there is normal to slightly decreased osteoclastic activity in conjunction with greatly decreased bone forming ability. This form of osteoporosis is thought to be caused by decreased osteoblast activity/function and has been attributed to various factors such as deficits in recruitment, proliferation and differentiation of these cells at needed sites, as well as changes in the milieu as a result of other age- related processes. It has been shown that there is no bone formation in mice in which the gene encoding the transcription factor for osteocalcin (a gene expressed only in osteoblasts) OSF2/Cbfal has been inactivated. We here propose to test the hypothesis that deficits in differentiated function and/or decreased proliferative ability due to cell senescence occurs with aging in osteoblast cells and contributes to age related osteoporosis. We will test this by determining OSF2/Cbfal expression, and expression of senescence related genes in bone tissue from young and old donors and proliferation potential as well as expression of these genes in osteoblasts derived from the bone. We will also determine whether osteoblasts can form tissue in a transplatation model system in vivo. The results will provide the preliminary data and evidence that we can perform these techniques for an R01 proposal.

临床上重要的骨质流失是I型骨质疏松症，II型骨质疏松症和次要原因的总和。在女性中，在35岁之前就达到了最大的骨骼质量，而小梁骨质流失的证据在更年期开始之前已经显而易见。在绝经后的期间，骨质流失率增加了大约5 - 10年，在此期间，由于II型骨质疏松症，骨质流失持续下降。在男性中，骨质流失率不如女性的快速，它是持久的，仅由于II型骨质疏松症以及次要原因。椎骨流失的纵向研究表明，骨质疏松症的速率相对较快，接近女性。骨质疏松症类型之间的差异很明显，但相对重要性尚不清楚。如果估计是正确的，那么每3名女性中有1人在九十岁时就会出现髋部骨折，而六分之一的男性则会出现髋部骨折。大于75岁的男性与髋部骨折有关的死亡率为30％，报告了三倍。因此，II型骨质疏松症是一个非常重要的公共卫生问题，不仅是为了对男性的健康状况的影响，而且还因为它在女性中所发挥的添加作用。在这种情况下，与骨形成能力大大降低的结合下，正常的骨骼活性略有降低。这种形式的骨质疏松症被认为是由成骨细胞活性/功能降低引起的，并且归因于各种因素，例如所需地点在所需地点的募集，增殖和分化的缺陷以及由于其他年龄相关过程而导致的环境变化。已经表明，在小鼠中没有骨形成，其中编码骨钙素转录因子的基因（仅在成骨细胞中表达的基因）OSF2/cbfal被灭活。我们在这里建议测试以下假设：在成骨细胞中，由于细胞衰老而导致的分化功能和/或降低的增殖能力的缺陷，并有助于与年龄相关的骨质疏松症。我们将通过确定OSF2/CBFAL的表达以及来自年轻人和老供体的骨组织中衰老相关基因的表达以及这些基因在骨骼中成骨细胞中的表达以及这些基因的表达。 我们还将确定成骨细胞是否可以在体内移植模型系统中形成组织。 结果将提供初步数据和证据，表明我们可以为R01提案执行这些技术。