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Reversing Age-related Bone Loss by Administration of the Matricellular Protein Cyr61/CCN1

通过施用基质细胞蛋白 Cyr61/CCN1 逆转与年龄相关的骨质流失

基本信息

批准号：
10703266
负责人：
XIAO-DONG CHEN
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703266
关键词：
Address Age Age-Related Bone Loss Aging Animal Model Apoptosis Architecture Attenuated BMP2 gene Binding Biological Assay Bone Density Bone Marrow Bone Matrix Bone Tissue Cells Data Defect Exhibits Extracellular Matrix Funding General Population Genetic Goals Healthcare Home Human Immunodeficient Mouse Impairment In Vitro Incubated Knock-out Knockout Mice Measures Metabolism Methods Mus Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteopenia Osteoporosis Patients Persons Population Positioning Attribute Property Proteins Proteomics Recombinants Rejuvenation Reporting Role Stromal Cells Testing Time Veterans Wild Type Mouse age related attenuation bone bone loss bone marrow mesenchymal stem cell bone mass comparative efficacy cyr61 protein double walled carbon nanotube efficacy evaluation human old age (65+)improved in vivo innovation military veteran mouse model novel novel strategies overexpression response self-renewal side effect stem cell aging stem cell niche stem cells stemness

项目摘要

Summary Previously, we reported that cell-free native extracellular matrix (ECM), synthesized by bone marrow (BM) stromal cells, significantly promoted the stemness of mouse and human BM-derived mesenchymal stem cells (BM-MSCs). More importantly, defects in self-renewal, differentiation, and bone formation capacity of aging BM- MSCs can be completely rescued by culture on young BM-ECM (i.e., made by cells from young donors). In contrast, old BM-ECM (i.e., made by cells from old donors) failed to support both young and old MSC self- renewal and differentiation capacity. By proteomic analysis, we found that the matricellular protein Cyr61 was abundant in young ECM but absent in old ECM. Subsequently, we used genetic methods to down- or up-regulate the incorporation of Cyr61 during synthesis of young or old BM-ECM and found that Cyr61-depleted young ECM lost its ability, while Cyr61-replenished old ECM gained its ability, to retain MSC properties. In addition, we showed that low bone mineral density (BMD) was associated with decreased amounts of Cyr61 in bone tissue of old mice. More interestingly, the presence of Cyr61 in bone is required for the anabolic effect of intermittent PTH that by itself up-regulates Cyr61 expression in old mice. The goal of the current proposal is to reverse age- related bone loss by replenishing a critical matricellular protein component, Cyr61/CCN1, to the aging bone microenvironment (i.e., stem cell niche). We hypothesize that replenishing Cyr61 to the aging bone matrix will restore the ability of the MSC microenvironment (niche) to support MSC self-renewal, differentiation, and bone formation capacity, resulting in an attenuation of bone loss and improvement in bone anabolic response to intermittent PTH treatment. We are uniquely positioned to test this hypothesis since, in addition to our strong preliminary data, we have established a unique animal model, bone-specific Cyr61 knockout out (Cyr61‒) mice, which displays osteopenia at an early age. To test the hypothesis, we will determine the effect of restoring Cyr61 to BM-ECM, produced by cells from Cyr61‒ or old wild type (wt) mice, on its ability to retain/rescue the quantity and quality of young-/old-BM-MSCs (Aim 1). Then we will determine the efficacy of recombinant Cyr61 (rCyr61), carried by multi-walled carbon nanotubes (MWCNTs), in reversing both stem cell quantity/quality and bone loss in Cyr61‒ and old wt mice (Aim 2). Finally, we will compare the efficacy of administering rCyr61 followed by intermittent PTH versus PTH alone at reversing bone loss in Cyr61‒ or old mice (Aim 3). The proposed study is highly innovative by testing our novel hypothesis via: 1) novel animal models, bone-specific Cyr61‒ and old wt mice (natural Cyr61 deficiency with aging), to determine if replenishing Cyr61 to the bone ECM can reverse BM- MSC function and bone loss; 2) a novel vehicle, MWCNTs, that specifically delivers rCyr61 to the bone matrix; and 3) testing the synergistic effects of Cyr61 administration prior to intermittent PTH on bone anabolic metabolism. The proposed study is significant because current osteoporosis treatments mainly focus on balancing osteoclast/osteoblast activity and have limited efficacy and considerable side effects. The studies have great potential to benefit both the veteran and general population by providing a new approach for treating osteoporosis that focuses on restoring the aging stem cell niche, which has not been explored previously.

总结

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Organ-specific extracellular matrix directs trans-differentiation of mesenchymal stem cells and formation of salivary gland-like organoids in vivo.

器官特异性的细胞外基质指导间充质干细胞的反差异，并在体内形成唾液腺样的类器官。

DOI：
10.1186/s13287-022-02993-y
发表时间：
2022-07-15
期刊：
Stem cell research & therapy
影响因子：
7.5
作者：
通讯作者：

Oral and Craniofacial Stem Cells: An Untapped Source for Neural Tissue Regeneration.

DOI：
10.1089/ten.tea.2020.0023
发表时间：
2020-03
期刊：
Tissue engineering. Part A
影响因子：
0
作者：
M. Marinković;Nicholas F. Dybdal-Hargreaves;T. Block;D. Dean;C. Yeh;Xiao-Dong Chen
通讯作者：
M. Marinković;Nicholas F. Dybdal-Hargreaves;T. Block;D. Dean;C. Yeh;Xiao-Dong Chen

Restoring the quantity and quality of elderly human mesenchymal stem cells for autologous cell-based therapies.