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

CaMKK2 抑制作为骨质疏松症的双效骨合成代谢和抗分解代谢疗法

基本信息

批准号：
9052878
负责人：
Uma Sankar
金额：
$ 33.73万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-18 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052878
关键词：
Acids Adult Age Aging Alleles Arrestins Biology Bone Diseases Bone Growth Bone Remodelling Pathway Bone Resorption Bone remodeling Ca(2+)-Calmodulin Dependent Protein Kinase Calcium/calmodulin-dependent protein kinase Cells Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Family member Fracture Generations Goals Hormones Hour Human Investigation Knockout Mice LDL-Receptor Related Protein 1 Label Mechanics Mediating Medical Messenger RNA Modeling Mus Operative Surgical Procedures Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Ovariectomy Parathyroid gland Partner in relationship Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Play Population Process Protein Kinase Proteins Proteomics Public Health RNA Regulation Reporting Role Sampling Signal Pathway Signal Transduction Teriparatide Testing Therapeutic Tumor necrosis factor receptor 11b United States Up-Regulation aged base beta catenin bone bone erosion bone loss bone mass bone strength fluorexon human disease inhibitor/antagonist innovation lipoprotein receptor related protein 5 long bone new therapeutic target novel nuclear factors of activated T-cells osteoblast differentiation public health relevance senescence socioeconomics substantia spongiosa therapeutic target tomography transcription factor

项目摘要

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.

描述（由申请人提供）：骨质疏松症是一种以骨量和骨强度的系统性损失导致脆性骨折为特征的疾病，由于骨重塑失衡而迅速成为美国的主要公共卫生威胁。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，因为骨质疏松症相当无症状，并且通常仅在患者持续显着的骨侵蚀后才被发现，因此治疗的目的是。然而，与构成当前抗骨质疏松症治疗支柱的高效抗骨吸收药物不同，刺激骨形成的药物在很大程度上仍然不发达。迫切需要新的治疗靶点，以刺激成骨细胞介导的骨生成并抑制破骨细胞的骨吸收，我们的初步研究确定了 Ca2+/钙调蛋白 (CaM) 依赖性。蛋白激酶激酶 2 (CaMKK2) 作为此类靶标之一，因为它的抑制会对合成代谢途径产生积极影响，并对骨重塑的分解代谢途径产生负面影响。CaMKK2 缺失的小鼠的长骨中骨小梁质量增强，成骨细胞数量显着增加且数量减少。此外，它的抑制作用可以保护小鼠免受卵巢切除引起的和与年龄相关的骨质疏松症的影响。拟议的研究将使我们能够确定 CaMKK2 调节的精确机制。成骨细胞和破骨细胞分化并设计其在骨质疏松症治疗中的潜在抑制策略，开发 CaMKK2 抑制作为新一代治疗靶点，促进骨量增长，同时抑制骨吸收，将代表抗骨质疏松症治疗的重大突破。