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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：
9761835
负责人：
Uma Sankar
金额：
$ 34.04万
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 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761835
关键词：
Acids Adult Age Aging Alleles Biology Bone Diseases Bone Growth Bone Remodelling Pathway Bone Resorption Bone remodeling Ca(2+)-Calmodulin Dependent Protein Kinase Cells Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Family member Generations Goals Hour Human Investigation Knock-in Mouse Knockout Mice LDL-Receptor Related Protein 1 Label Mechanics Mediating Medical Messenger RNA Modeling Mus Operative Surgical Procedures Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Ovariectomy PTH gene Partner in relationship Pathologic Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacology Phosphotransferases Play Population Process Proteins Proteomics Public Health RNA Regulation Reporting Role Sampling Signal Pathway Signal Transduction Testing Therapeutic Tumor necrosis factor receptor 11b United States Up-Regulation aged baby boomer base beta catenin beta-arrestin bone bone erosion bone loss bone mass bone strength cortical bone fluorexon fragility fracture human disease inhibitor/antagonist innovation lipoprotein receptor related protein 5 long bone new therapeutic target novel nuclear factors of activated T-cells osteoblast differentiation parathyroid hormone (1-34)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全身性骨量和强度丧失为特征导致脆性骨折的疾病，在美国正迅速成为一个主要的公共健康威胁。骨质疏松症是由骨重建失衡引起的，骨重建的特征是成骨细胞介导的骨合成和破骨细胞介导的骨吸收。由于骨质疏松症相当无症状，通常只有在患者遭受严重的骨侵蚀后才能被发现，因此旨在恢复被侵蚀的骨的治疗与针对骨吸收的治疗同等重要。然而，与构成当前抗骨质疏松治疗主流的高效抗吸收药物不同，刺激骨形成的药物在很大程度上仍然不发达。因此，迫切需要新的治疗靶点，既能刺激成骨细胞介导的骨积累，又能抑制破骨细胞性骨吸收。我们的初步研究发现，钙/钙调素依赖的蛋白激酶2(CAMKK2)就是这样一个靶点，因为它的抑制积极影响合成代谢途径，负面影响骨重建的分解代谢途径。CAMKK2基因缺失的小鼠其长骨中的骨小梁数量增加，成骨细胞数量显著增加，多核破骨细胞减少。此外，抑制其对卵巢切除引起的小鼠骨质疏松和与年龄相关的骨质疏松具有保护作用。这些研究将使我们能够确定CAMKK2调节成骨细胞和破骨细胞分化的确切机制，并设计出潜在的抑制其治疗骨质疏松症的策略。开发CAMKK2抑制剂作为新一代治疗靶点，在抑制吸收的同时促进强健的骨量增加，将是抗骨质疏松治疗的重大突破。