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Abstract：
Paget\'s disease of bone (PDB) is the second most prevalent metabolic bone disorder worldwide, with a prevalence rate of 1.5%-8.3%. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Typically, PDB develops in the later stages of life, particularly in the late 50s, and affects men more frequently than women. PDB is a complex disease influenced by both genetic and environmental factors. PDB has a complex genetic basis involving multiple genes, with SQSTM1 being the gene most frequently associated with its development. Mutations affecting the UBA domain of SQSTM1 have been detected in both familial and sporadic PDB cases, and these mutations are often associated with severe clinical expression. Germline mutations in other genes such as TNFRSF11A, ZNF687 and PFN1, have also been associated with the development of the disease. Genetic association studies have also uncovered several PDB predisposing risk genes contributing to the disease pathology and severity. Epigenetic modifications of genes involved in bone remodelling and regulation, including RANKL, OPG, HDAC2, DNMT1, and SQSTM1, have been implicated in the development and progression of Paget\'s disease of bone, providing insight into the molecular basis of the disease and potential targets for therapeutic intervention. Although PDB has a tendency to cluster within families, the variable severity of the disease across family members, coupled with decreasing incidence rates, indicates that environmental factors may also play a role in the pathophysiology of PDB. The precise nature of these environmental triggers and how they interact with genetic determinants remain poorly understood. Fortunately, majority of PDB patients can achieve long-term remission with an intravenous infusion of aminobisphosphonates, such as zoledronic acid. In this review, we discuss aspects like clinical characteristics, genetic foundation, and latest updates in PDB research.
摘要：
佩吉特骨病(PDB)是世界范围内第二大最普遍的代谢性骨病,患病率为1.5%-8.3%。它的特点是局部区域加速，杂乱无章,和过度的骨骼生产和周转。通常,PDB在生命的后期发展，尤其是在50年代末，影响男性比女性更频繁。PDB是一种受遗传和环境因素共同影响的复杂疾病。PDB具有复杂的遗传基础，涉及多个基因，SQSTM1是最常见的与其发育相关的基因。在家族性和散发性PDB病例中均检测到影响SQSTM1UBA结构域的突变，这些突变通常与严重的临床表达有关。其他基因如TNFRSF11A的种系突变，ZNF687和PFN1也与疾病的发展有关。遗传关联研究还发现了一些导致疾病病理和严重程度的PDB易感风险基因。参与骨重塑和调节的基因的表观遗传修饰，包括RANKL,OPG,HDAC2、DNMT1和SQSTM1参与了Paget骨病的发生和发展,深入了解疾病的分子基础和治疗干预的潜在目标。尽管PDB有聚集在家庭中的趋势，不同家庭成员的疾病严重程度，加上发病率下降，表明环境因素也可能在PDB的病理生理学中起作用。这些环境触发因素的确切性质以及它们如何与遗传决定因素相互作用仍然知之甚少。幸运的是,大多数PDB患者可以通过静脉输注氨基二膦酸盐获得长期缓解，如唑来膦酸。在这次审查中,我们讨论临床特征等方面，遗传基础,以及PDB研究的最新更新。
