破骨细胞增生过度是导致骨质丢失的主要原因，临床上常见于骨质疏松症、Paget’s病等疾病。从分子机制研究骨破坏的潜在原因是治疗溶骨性疾病至关重要的策略。我们通过筛查乙酰基亚硝基脲（ENU）诱导的突变小鼠骨骼表型，进而确认其是调节骨质平衡的关键分子。前期研究实验证实ENU诱变小鼠Roquin的新型突变，表现出严重病理性骨丢失、破骨细胞生成异常增多、T细胞RANKL表达增加。通过这些新发现，本研究假设Roquin蛋白在骨代谢中起到至关重要的作用。为了证实该假设，提出3个具体研究目标：Roquin突变小鼠骨骼系统组织形态学改变和生物力学特性；Roquin在破骨细胞分化、骨重吸收中的生理学作用和对RANKL细胞通路的调节作用； Roquin突变致骨丢失的骨免疫学机制。探讨Roquin影响骨密度的机制，尤其是其在破骨细胞形成和功能的分子调节机制，将为临床治疗骨质疏松症提供新的治疗思路。

Pathological bone loss induced by excessive osteoclast formation is the major mechanism underlying many debilitating bone diseases, including osteoporosis, Paget’s disease, lupus, and aseptic loosening of orthopaedic implants. To understand the root cause of bone destruction as well as its molecules involved is vital for an improved therapeutic strategy against osteolytic bone diseases. To gain insights into the molecular genetics and mechanisms of bone loss, we have screened for bone phenotypes in chemical (ENU)-induced mutant mice to identify key molecules that regulate bone homeostasis. We have uncovered one mouse line which carries a M199R mutation in the Roquin gene, and exhibits severe bone loss. Preliminary data show that the Roquin mutant mice display substantial bone loss with reduced trabecular and cortical bone volume; an increase of TRACP positive cells in vivo and osteoclastogenesis in vitro; and an increase of RANKL gene expression in T cells. Based on these intriguing and novel observations we hypothesize that Roquin plays a critical role in bone homeostasis by intrinsic and extrinsic mechanisms. In order to test this hypothesis, three specific aims are proposed: 1) To characterize the bone phenotype of Roquin mice；2) To determine the physiological role of Roquin in osteoclast differentiation and bone resorption, and identify the molecular regulation of Roquin as a RING-type E3 ubiquitin ligase in RANKL signaling pathways；3) To investigate the extrinsic mechanism of bone loss in Roquin mutant mice via activated T cells in osteoimmunology. This research may provide a new way for the treatment of osteoporosis by investigating the molecular mechanism of Roquin in bone mineral density, osteoclastogenesis, and osteoclast fuction.