The Role of P62/A170 in Pathological Bone Destruction

在澳大利亚，约有30%的患者因与骨骼疾病有关的原因而被送往公立医院，包括创伤、骨关节炎、骨质疏松症、原发性和继发性骨肿瘤、遗传和代谢疾病。异常骨吸收导致大多数这些疾病和病症。基于佩吉特病患者P62突变的临床证据和我们对P62参与RANKL诱导的NF-κ B信号传导的观察，我们提出细胞内分子P62-A172可能在骨吸收细胞吸收骨所必需的开关信号中起重要作用。为此，我们将研究P62的分子机制，以及与其可能的合作伙伴的相互作用，促进异常骨吸收。本课题的临床意义在于：1）提高对骨科相关疾病中骨吸收异常的认识。2)为治疗这些疾病和病症提供药物开发策略。

Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement of P62 in RANKL-induced NF-Kb signaling, we propose that intracellular molecule P62-A172 may play an important part in the switch off-on signals necessary for bone resorbing cells to resorb bone. To this end, we will study the molecular mechanism of P62 in action, and the interaction with its possible partners for the facilitation of abnormal bone resorption. The clinical significance of this project is to: 1) enhance understanding of abnormal bone resorption in Orthopaedic related diseases and conditions. 2) provide a strategy of drug development for the treatment of these disease and conditions.