迄今对Blimp1-BCL6信号通路在调节破骨细胞分化和维持骨稳态中具关键作用没有引起足够关注，是因该信号通路异常调控并没在人体疾病中得到证实。我们前期发现"骨质疏松伴肢端骨溶解"新综合征家系，对患病兄弟2人全外显子组测序，获得BCOR致病基因K1029R突变。BCOR是BCL6共结合阻遏因子。前期预实验证实：K1029R突变导致破骨细胞NFATc1通路活化；BCOR与BCL6结合力下降等。由此我们推测BCOR基因K1029R突变导致X-连锁隐性遗传骨质疏松伴肢端骨溶解综合征，可能经Blimp1-BCOR-BCL6信号通路对破骨细胞调控发生异常，使破骨细胞功能和骨吸收显著增强。为此，本课题拟通过体外细胞实验和特定组织表达BCOR-K1029R点突变小鼠的整体实验，以阐明BCOR基因K1029R突变对Blimp1-BCOR-BCL6信号通路在调控破骨细胞功能及骨质疏松和骨溶解的发病机制。

So far, the role of Blimp1-BCL6 signaling pathway in the regulation of osteoclast differentiation and the maintenance of bone homeostasis has not attracted enough attention, because abnormal regulation of this pathway has not been confirmed in human diseases. We used an exome-sequencing strategy and identified a pathogenic BCOR mutation (K1029R) in two brothers with a new osteoporosis with acro-osteolysis syndrome. Bcor is a Bcl6 corepressor factor. In our previous study, we found that the K1029R mutation led to activied NFATc1 pathway on osteoclast, and decreased BCOR interaction with BCL6. Therefore, we hypothesize that the BCOR gene K1029R mutation causes this X-linked recessive osteoporosis with acro-osteolysis syndrome through Blimp1-BCOR-BCL6 signaling pathway, which enhances osteoclast function and leads to a phenotypes of osteoporosis with acro-osteolysis. Therefore, we intend to use in vitro experiments and knockin mouse model to clarify the exact molecular mechanism of the BCOR gene K1029R mutation in the Blimp1-BCOR-BCL6 signaling pathway in the regulation of osteoclast function, and in the pathogenesis of osteoporosis with acro-osteolysis. The present study will provide an important basis for research and development of therapy through this signaling pathway for diseases with increased activity of osteoclast function such as osteoporosis.