Regulation of age-related bone loss by PKIgamma

PKIgamma 调节与年龄相关的骨质流失

• 批准号: 10208697
• 负责人: EDWARD M. GREENFIELD
• 金额: $ 41.1万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10208697
• 关键词: Adult; Affect; Age; Age-Related Bone Loss; Apoptosis; Bone Resorption; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Elderly man; Elderly woman; Enterobacteria phage P1 Cre recombinase; Equilibrium; FDA approved; Family member; Female; Forteo; Fracture; Fracture Healing; Future; Genetic; Goals; Homeostasis; In Vitro; Injections; Lead; LoxP-flanked allele; Mediating; Mus; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Ovariectomy; PTH gene; Patients; Pharmaceutical Preparations; Postmenopause; Process; Regulation; Role; Signal Transduction; Site; Testing; Tissues; Woman; age related; aged; bone; bone loss; healing; in vivo; knock-down; lipid biosynthesis; men; osteoprogenitor cell; progenitor; promoter; protein kinase inhibitor; response; senescence; sex; skeletal; spine bone structure; substantia spongiosa; therapeutic target; young adult

ABSTRACT Age-related trabecular bone loss begins in young adulthood and leads to increased rates of osteoporosis and fractures in elderly men and women. It is fastest in vertebrae, where it is ~2-fold faster in women than in men, and then accelerates in post-menopausal women. Stimulation of cAMP/PKA signaling by intermittent Parathyroid Hormone-like (iPTH) drugs (teriparatide or abaloparatide) is the only FDA-approved osteoporosis therapy that acts by increasing anabolic bone formation rather than by decreasing bone resorption. However, not all patients respond, therapy is limited to 24 months, and the anabolic effects are not maintained after cessation. Moreover, iPTH therapy requires daily injection and is extremely expensive (~$30,000/year). We previously discovered that knockdown or deletion of Protein kinase inhibitor  (Pkig) increases the anabolic processes induced by PTH/PKA in vitro. Targeting PKI might therefore increase the magnitude of response, or the percent of patients who respond, to iPTH therapy. Because the in vivo roles of PKI and the other two PKI family members were previously unknown, we generated Pkig-/- mice. Our preliminary results indicate that genetic deletion of Pkig overcomes both the age-related loss of bone volume and the age-related decline in skeletal healing. Our long-term goal is therefore to determine whether PKI is a potential therapeutic target, either alone or in combination with iPTH, to overcome age-related bone loss, the age-related decline in skeletal healing, and/or post-menopausal bone loss. Our overall hypothesis is that PKI mediates age-related bone loss and the age-related decline in skeletal healing by regulating the balance between osteogenesis and adipogenesis in a sex- and skeletal site-dependent manner. The overall hypothesis will be tested by the following Aims: Aim 1: Determine whether the effects of Pkig deletion on bone homeostasis depend on age, skeletal site, sex, and/or iPTH therapy. Aim 2: Determine mechanisms that are critical for regulation of age-related bone loss by PKI. Aim 3: Determine whether Pkig deletion (either alone or in combination with iPTH) overcomes the age-related decline of fracture healing and/or ovariectomy (OVX)-induced bone loss.

摘要 骨质疏松症相关的骨小梁丢失开始于年轻的成年期，并导致骨质疏松症的发生率增加， 老年男性和女性的骨折。它在椎骨中最快，女性比男性快2倍， 然后在绝经后妇女中加速。间歇性甲状旁腺激素对cAMP/PKA信号通路的刺激作用 激素样（iPTH）药物（teriparlitazone或abaloparlitazone）是FDA批准的唯一一种骨质疏松症治疗药物， 通过增加合成代谢骨形成而不是通过减少骨吸收起作用。然而，并非所有患者 反应，治疗仅限于24个月，停止后合成代谢的影响不会维持。此外，委员会认为， iPTH治疗需要每天注射，而且极其昂贵（~ 30，000美元/年）。我们之前发现， 蛋白激酶抑制剂Pkig（Pkig）的敲低或缺失增加了PTH/PKA诱导的合成代谢过程 体外因此，以PKI为目标可能会增加反应的幅度，或者增加患者的百分比， 对iPTH治疗有反应。由于PKI的基因组和其他两个PKI家族成员的体内作用， 在先前未知的情况下，我们产生了Pkig-/-小鼠。我们的初步结果表明，Pkig基因的缺失， 克服了与年龄相关的骨体积损失和与年龄相关的骨骼愈合下降。 因此，我们的长期目标是确定PKI是否是一个潜在的治疗靶点，无论是单独还是联合 与iPTH组合，以克服年龄相关的骨丢失、年龄相关的骨骼愈合下降，和/或 绝经后骨质流失我们的总体假设是，PKI介导年龄相关的骨丢失， 通过调节骨生成和脂肪生成之间的平衡， 性别和骨骼部位依赖性方式。将通过以下目的检验总体假设： 目的1：确定Pkig缺失对骨稳态的影响是否取决于年龄、骨骼部位、性别， 和/或iPTH疗法。 目的2：确定PKI对年龄相关性骨丢失调节的关键机制。 目的3：确定Pkig缺失（单独或与iPTH联合）是否克服了年龄相关的 骨折愈合下降和/或卵巢切除术（OVX）引起的骨丢失。