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REGULATION OF BONE FORMATION BY OSTEOCLASTS

破骨细胞对骨形成的调节

基本信息

批准号：
7650703
负责人：
MERRY JO OURSLER
金额：
$ 27.46万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7650703
关键词：
Acute Age Aging Attenuated BMP6 gene Binding Biological Assay Biology Bone Marrow Cells Bone Resorption Cell Survival Cells Cellular Assay Chronic Clinical Research Collaborations Conditioned Culture Media Coupled Coupling Data Defect Estrogens Gene Expression Goals Health Human In Vitro Knowledge Laboratories Lead Location Mediating Menopause Mesenchymal Mesenchymal Stem Cells Molecular Molecular Biology Mus Nodule Osteoblasts Osteoclasts Osteogenesis Phase Phosphorylation Physiology Play Positioning Attribute Postmenopause Process Production Recruitment Activity Regulation Reporting Research Research Personnel Resort Role SPHK1 enzyme Site Sphingosine Staging Stromal Cells TNFSF11 gene Testing Transforming Growth Factor beta Work age effect aged aging population bone bone loss bone metabolism bone morphogenetic protein 6 bone turnover c-myc Genes cell motility design effective therapy expectation in vivo in vivo Model insight migration mineralization mouse model neutralizing antibody novel osteoblast differentiation osteoclastogenesis progenitor response skeletal sphingosine 1-phosphate stem stem cell differentiation transcription factor USF

项目摘要

Bone resorption and bone formation appear to be tightly coupled. To explore osteoclast influences on osteoblast recruitment and differentiation, we examined osteoclast conditioned media (CM) for influences on osteoblasts. Osteoclast CM stimulated human mesenchymal stem (hMS) cell mineralized nodule formation. We identified candidate osteoclast-derived coupling factors using Affymetrix microarray. We observed induction of sphingosine kinase 1 (SPHK1), WntlOb, and BMP6 in mature multinucleated osteoclasts as compared to pre-osteoclasts. Stimulation of hMS cell nodule formation by the osteoclast CM was attenuated by the Wnt antagonist, Dkk1, a BMP-6 neutralizing antibody, and by a S1P antagonist. Sclerostin expression was elevated in osteoclast precursors and rapidly down-regulated during differentiation. CM from osteoclasts generated in vitro from 18-month old mice was unable to support hMS cell mineralization. TGF-beta treatment elevated SPHK1 and WntlOb expression. Our central hypothesis is that osteoclast production of SPHK1, WntlOb, and BMP6, combined with decreased Sclerostin expression, promotes osteoblast precursor recruitment, proliferation, differentiation, and survival and that each factor plays an integral role in maintaining coupling between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. In Aim 1, we will use functional cell assays and gene expression to ascertain the mechanisms by which osteoclast-derived coupling factors promote osteoblast gene expression, recruitment, proliferation, differentiation, and survival in vitro. In Aim 2 we will use molecular approaches to determine the mechanisms by which Sclerostin, SPHK1, WntlOb, and BMP6 are modulated during osteoclast differentiation in vitro. In Aim 3 we will use an in vivo model to examine the role of TGF-beta regulation of coupling factor production on osteoclast-mediated coupling of bone resorption to bone formation. In Aim 4 we will examine gene expression and cellular assays to resolve the contribution of age in osteoclast support of osteoblast maturation and mineralization. Together, these studies will provide important novel information on how osteoclasts control osteoblast-mediated bone formation.

骨吸收和骨形成似乎是紧密耦合的。目的：探讨破骨细胞对骨损伤的影响