软骨下骨重塑是骨性关节炎的重要特征。破骨细胞作为人体内唯一具有骨吸收功能的细胞，功能状态与软骨下骨重塑密切相关。项目组研究发现BRD4在RANKL诱导的破骨细胞分化过程中表达逐渐增高，BRD4抑制剂JQ1显著抑制破骨细胞分化，破骨细胞特异性BRD4条件性敲除小鼠软骨下骨表现为骨硬化表型，提示BRD4在软骨下骨重塑过程中发挥重要功能。此外，项目组发现HMGB1是BRD4的直接作用靶点，而HMGB1重组蛋白可以显著促进破骨细胞分化成熟。结合上述工作基础，本研究将系统分析：1.BRD4条件性基因敲除的骨骼表型及BRD4对破骨细胞分化功能的影响；2.破骨分化过程中BRD4对HMGB1的调控作用；3.研究BRD4对于骨性关节炎小鼠膝关节软骨下骨重塑的调控作用；4.研究BRD4抑制剂CPI-203对骨性关节炎小鼠软骨下骨重塑的挽救作用。本研究为临床治疗破骨细胞介导的软骨下骨重塑提供了新的分子靶点。

Subchondral bone remodeling is an important feature of osteoarthritis (OA). As the only cells type that are capable of bone resorption, the function of osteoclasts (OCs) are closely related to the remodeling of subchondral bone. Our previous study found that the expression level of BRD4 gene, a member of bromodomain and extra-terminal (BET) family proteins, was increased gradually in RANKL induced OCs differentiation and maturation. Furthermore, BRD4 inhibitor JQ1 could reduce the differentiation and maturation of Ocs. To further construct osteoclast specific BRD4 gene conditional knockout (cKO) mice, We found that the knee joint subchondral bone of BRD4 cKO mice exhibit an increased bone mass with characteristics most consistent with osteopetrosis phenotype. Those results suggesting that BRD4 may plays an important role in OCs-mediated subchondral bone remodeling. In addition, we previously demonstrated that HMGB1 is a direct down stream target of BRD4, while the recombination HMGB1 protein promoted the differentiation and maturation of OCs. Based on these novel observations, this studies we aim to: 1. Analysis the skeletal phenotype of BRD4 cKO mice comprehensively and confirm the physiological role of BRD4 in OC-mediated bone resorption in vitro; 2. Determine the regulation mechanism between BRD4 and HMGB1 during OCs maturation; 3. Investigate the role of BRD4 in subchondral bone remodeling of knee joint in an ACLT-induced OA model; 4. Explore the potential rescue effects of BRD4 inhibitor CPI-203 on subchondral bone remodeling in ACLT OA mice. The further investigation of this project will potentially identify novel molecular targets for OC mediated subchondral bone remodeling in osteoarthritis.