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Mechanisms of bone fragility in Autosomal Dominant Osteopetrosis type II: from human to mouse and back

常染色体显性骨硬化症 II 型骨脆性机制：从人到小鼠再到背部

基本信息

批准号：
10366576
负责人：
Thomas Levin Geiser Andersen
金额：
$ 49.48万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366576
关键词：
Affect Age Albers-Schonberg disease Antibody Therapy Automobile Driving Back Biomechanics Biopsy Specimen Bone Diseases Bone Marrow Transplantation Bone Resorption Bone remodeling Bone structure CD14 gene Caring Cell Nucleus Cells Characteristics Coculture Techniques Communication Complement Computer Assisted Coupling Data Development Disease Elderly Endosteal Cell Family Future Genes Genetic Transcription Goals Human Image In Situ Hybridization In Vitro Inherited Investigation Knowledge Mature Bone Mediating Molecular Mus Mutation Osteoblasts Osteoclasts Osteogenesis Osteoporosis Pathologic Patients Peripheral Phenotype Physiological Physiology Process Resources Sampling Scallop Skeletal bone TNFSF11 gene Testing Withdrawal Work base bone bone fragility bone loss bone mass cell type cost human model in vivo innovation insight lens monocyte mouse model multimodality novel novel therapeutics overexpression progenitor programs sex skeletal therapeutic target tool transcriptome sequencing transcriptomics translational impact treatment strategy

项目摘要

SUMMARY Coupling, or communication between the bone-resorbing osteoclasts and bone-forming osteoblasts during bone remodeling, is a key step in the bone remodeling cycle. While compelling evidence shows that bone loss and fragility with age and osteoporosis result from corrupted coupling, the precise mechanism of osteoclast- osteoblast communication remains unclear. Thus, although stimulating coupling is a theoretically attractive therapeutic target, current treatments for osteoporosis, a common disorder affecting 54 million of the elderly in the US alone, are limited to either inhibiting osteoclastic bone resorption or stimulating osteoblastic bone formation. Our long-term goal is to determine the mechanism of osteoclast-osteoblast communication critical for coupling of bone formation to resorption during physiological bone remodeling, using rare osteopetrotic diseases as a tool. Rare bone diseases provide important insights into typical bone physiology and knowledge gained from these diseases has already led to new therapies for osteoporosis. In this proposal, we utilize samples from patients with autosomal dominant osteopetrosis type II (ADOII), a rare inheritable osteopetrosis characterized by high bone mass and skeletal fragility and complement human studies with mouse models. ADOII results from heterozygous mutations in the CLCN7 gene, which encodes the ClC-7 Cl-/H+ exchanger essential for osteoclastic bone-resorption. While the lack of osteoclastic resorption clearly contributes to bone phenotype, bone formation is also inappropriately high. In preliminary data investigating the bone structural unit (BSU) composition of ADOII bones, we found bone formation is primarily remodeling based, with excess bone formation called overflow remodeling. Osteoclasts are abundant and scalloped cement lines suggest an intermittent pit-like resorption mode, which in combination with overflow remodeling results in a characteristic puzzle-like bone structure. We hypothesize that the anabolically active but poorly resorptive osteoclasts in ADOII overexpress anabolic coupling factors, inappropriately stimulating bone formation to overfill the resorbed cavities and leading to disorganized puzzle-like bone and fragility. We will test this hypothesis by combining in vivo and in vitro studies of ADOII patients and mouse models, multimodal and multiscale imaging, biomechanics and spatial/single-nuclei transcriptomics. Specifically, we will: 1) test if the high bone mass and fragility in human and mouse ADOII is osteoclast-mediated; and 2) investigate the mechanism of inappropriately high bone formation in ADOII by single nuclei transcriptomic analysis of physically adjacent osteoclasts and osteoblasts. The proposed studies take advantage of the unique resource of extant iliac crest bone biopsy specimens from 15 ADOII patients from a Danish family carrying the CLCN7 (G215R) mutation and age and sex matched controls, and two mouse models of ADOII, including the analogous Clcn7G213R/+ mutation. Through the lens of ADOII, these studies will provide unique insights into osteoclast-osteoblast communication.

总结