Regulation of age-related bone loss by PKIgamma

摘要 与年龄相关的骨小梁丢失始于青年时期，导致骨质疏松症和骨质疏松症的发生率增加 老年男性和女性的骨折。它在脊椎中最快，女性的速度是男性的2倍左右， 然后在绝经后的女性中加速。间歇性甲状旁腺对cAMP/PKA信号的刺激作用 激素样(IPTH)药物(Teriparatide或abaloparatide)是FDA批准的唯一一种治疗骨质疏松症的药物 通过促进合成代谢骨形成而不是通过减少骨吸收而起作用。然而，并不是所有的患者 治疗以24个月为限，停药后合成代谢作用不再维持。此外， IPTH治疗需要每天注射，而且非常昂贵(约30,000美元/年)。我们之前发现， 蛋白激酶抑制剂(Pkig)的敲除或缺失可增加甲状旁腺素/蛋白激酶A诱导的合成代谢过程 在试管中。因此，以pki为靶点可能会增加反应的幅度，即患者 对iPTH治疗有反应。因为pki和另外两个pki家族成员在体内的作用是 在之前未知的情况下，我们产生了Pkig-/-小鼠。我们的初步结果表明，Pkig的基因缺失 克服了与年龄相关的骨骼体积的丧失和与年龄相关的骨骼愈合能力的下降。 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，无论是单独还是在 与iPTH联合使用，以克服与年龄相关的骨丢失、与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介导了与年龄相关的骨丢失和 通过调节成骨和成脂之间的平衡，年龄相关的骨骼愈合下降 性别和骨骼部位依赖的方式。总体假设将通过以下目标进行检验： 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治疗。 目的2：确定PKI调节增龄性骨丢失的关键机制。 目标3：确定Pkig缺失(单独或与iPTH联合)是否克服了年龄相关性 骨折愈合下降和/或卵巢切除(OVX)导致的骨丢失。

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.