CaMKK2 Inhibition as a Dual-Action Bone Anabolic and Anti-Catabolic Therapy in Osteoporosis

 描述（由申请人提供）：骨质疏松症是一种以骨量和强度的全身性损失为特征的疾病，导致脆性骨折，正迅速成为美国主要的公共卫生威胁。骨质疏松症是由骨重建失衡引起的，骨重建是一个以成骨细胞介导的骨合成和破骨细胞介导的骨吸收为特征的过程。因为骨质疏松症是相当无症状的，并且通常仅在患者持续显著的骨侵蚀后才被检测到，所以旨在恢复侵蚀骨的治疗与针对骨吸收的治疗同样重要。然而，与形成当前抗骨质疏松症疗法的主要支柱的抗再吸收药物的高效库不同，刺激骨形成的药物在很大程度上仍然不发达。因此，迫切需要新的治疗靶点，其将刺激成骨细胞介导的骨积聚以及抑制骨细胞骨吸收。我们的初步研究确定了Ca 2 +/钙调蛋白（CaM）依赖性蛋白激酶激酶2（CaMKK 2）作为一个这样的目标，因为它的抑制积极影响合成代谢途径和消极影响骨重建的分解代谢途径。缺乏CaMKK 2的小鼠在其长骨中具有增强的骨小梁质量，沿着具有显著较高数量的成骨细胞和较少的多核破骨细胞。此外，它的抑制提供了保护，从卵巢切除术诱导的和年龄相关的骨质疏松症的小鼠。这些研究将使我们能够确定CaMKK 2调节成骨细胞和破骨细胞分化的确切机制，并制定其抑制治疗骨质疏松症的潜在策略。开发CaMKK 2抑制剂作为新一代治疗靶点，促进稳健的骨量增加，同时抑制骨吸收，将代表抗骨质疏松治疗的重大突破。

 DESCRIPTION (provided by applicant): Osteoporosis, a disease characterized by the systemic loss of bone mass and strength resulting in fragility fractures, is rapidly poised to become a major public health threat in the United States. Osteoporosis results from imbalances in bone remodeling, a process characterized by osteoblast-mediated bone synthesis and osteoclast-mediated bone resorption. Because osteoporosis is fairly asymptomatic, and is often detected only after the patient has sustained significant bone erosion, therapies aimed at restoring the eroded bone are equally important as those that target bone resorption. However, unlike the highly efficient repertoire of anti- resorptive drugs that form the mainstay of the current anti-osteoporosis therapy, drugs that stimulate bone formation remain largely underdeveloped. Hence there is a critical need for novel therapeutic targets that will stimulate osteoblast-mediated bone accrual together with the inhibition of osteoclastic bone resorption. Our preliminary studies identify Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) as one such target as its inhibition positively impacts anabolic pathways and negatively impacts catabolic pathways of bone remodeling. Mice null for CaMKK2 possess enhanced trabecular bone mass in their long bones, along with significantly higher numbers of osteoblasts and fewer multinuclear osteoclasts. Moreover, its inhibition offers protection from ovariectomy-induced and age-associated osteoporosis in mice. The proposed studies will enable us to define the precise mechanism by which CaMKK2 regulates osteoblast and osteoclast differentiation and devise potential strategies of its inhibition in the treatment of osteoporosis. Development of CaMKK2 inhibition as a new generation therapeutic target that promotes robust bone mass accrual while inhibiting resorption will represent a major breakthrough in anti-osteoporosis treatment.