miR-17-92调控成骨细胞功能的分子信号网络及其在骨质疏松症中的病理作用

Osteoporosis is the most common bone metabolism disorder in elder population. We are shorting of reliable diagnostic methods and efficient treatment for osteoporosis. mircoRNAs are a type of novel RNA molecules that critically regulate osteoblast proliferation and differentiation, and may service as a new tool for osteoporosis. Our preliminary studies show that miR-17 ~ 92 cluster is down-regulated along with osteoblast differentiation. Heterozygous detetion of miR-17 ~ 92 cluster in whole body （miR-17-92fl/Δ）and homozygous deletion of miR-17 ~ 92 cluster in osteoblast result in lower bone mineral content, bone mineral density and abnormal osteoblast functions. miR-17-92fl/Δ mice are resistant to bone loss induced by glucocorticoid. miR-17 ~ 92 cluster is down-regulated in bone from patients with postmenopausal osteoporosis. These results suggest that miR-17 ~ 92 cluster regulates osteoblast function and plays important role in the pathogenesis of osteoporosis. This proposal is going to determine the regulation roles of miR-17 ~ 92 cluster in osteoblasts under normal and pathological conditions, the molecular network connected to the regulation through transgenic and conditional knockout anamial models and cell models, and to determine the pathogenesis of the molecular network in osteoporosis through clinical studies. The research will supply theoretical basis and novel targets for osteoporosis.

骨质疏松症是严重威胁中老人健康的最常见代谢性骨病，尚缺乏可靠的早期诊断方法和高效药物。miRNA为转录后负调节基因表达的新型小分子，在成骨细胞增殖分化中发挥重要调控作用，为骨质疏松症的诊治开辟了新领域。申请者发现成骨细胞的分化成熟伴随miR-17~92表达下调；miR-17~92全身杂合敲除和成骨细胞内定向敲除的基因工程鼠表现为骨量减少、骨密度降低、成骨细胞功能异常； miR-17~92缺陷鼠抵抗糖皮质激素诱导的骨丢失；miR-17~92在绝经后骨质疏松症骨组织呈低表达，提示miR-17~92调控成骨细胞功能并在骨质疏松症中发挥重要病理作用。申请者拟通过成骨细胞内miR-17~92过表达/基因定向敲除的基因工程鼠、细胞模型及骨质疏松症病例深入研究miR-17~92在生理病理状态下对成骨细胞功能的调控、调控的分子信号网络及其在骨质疏松症中的病理作用，旨在为骨质疏松症的诊治提供新的思路和方法。

最近的研究标明miR-17-92与骨骼发育和骨代谢密切相关，但具体的信号通路尚不清楚。课题组围绕miR-17-92 调控成骨细胞功能的分子信号网络这一中心任务，从细胞、基因工程鼠及临床病例三方面开展研究，发现成骨细胞分化过程中miR-17~92表达量逐渐下调，成骨细胞内miR-17~92缺失后其增殖和成骨能力降低，骨特异性基因Runx2和I型胶原的表达显著降低，小鼠的骨矿物密度、骨量及骨小梁数量显著降低；而破骨细胞内miR-17~92缺失后小鼠的骨矿物密度、骨量及骨小梁数量显著增加，破骨细胞的骨吸收能力降低、但其表达破骨/成骨偶联因子CTHRC1显著升高，导致成骨细胞功能增强、骨特异性基因Runx2和I型胶原的表达增加；通过临床研究发现绝经后骨质疏松患者血液中骨吸收指标CTX值和血浆hsa-miR-20a、hsa-miR-19b、 hsa-miR-17-5p、 hsa-miR-19a和 hsa-miR-18a表达正相关， 骨形成指标N-MID值与hsa-miR-20a、hsa-miR-19b和hsa-miR-19a表达正相关。通过研究证实了miR-17-92 对成骨和破骨具有双向调节作用、同时通过偶联因子CTHRC1调节成骨细胞功能活动，血清中miR-17-92水平与骨代谢密切相关。在国家自然基金的资助下，课题组已经发表学术论文26篇（其中SCI收录论文18篇），参加国际国内学术会议并进行大会发言总共12次；获得奖励2项，培养研究生5名。