Banaganapalli Babajan, Fallatah Ibrahim, Alsubhi Fai, Shetty Preetha Jayasheela, Awan Zuhier, Elango Ramu, Shaik Noor Ahmad
Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
Front Genet. 2023 Apr 26;14:1131182. doi: 10.3389/fgene.2023.1131182. eCollection 2023.
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.
骨佩吉特病（PDB）是全球第二常见的代谢性骨病，患病率为1.5%-8.3%。其特征是局部区域骨生成和骨转换加速、紊乱且过度。通常，PDB在生命后期发病，尤其是在50多岁时，男性比女性更易患病。PDB是一种受遗传和环境因素影响的复杂疾病。PDB具有复杂的遗传基础，涉及多个基因，其中SQSTM1是与其发病最常相关的基因。在家族性和散发性PDB病例中均检测到影响SQSTM1 UBA结构域的突变，这些突变通常与严重的临床表现相关。其他基因如TNFRSF11A、ZNF687和PFN1的种系突变也与该疾病的发生有关。遗传关联研究还发现了几个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，与骨佩吉特病的发生和发展有关，为该疾病的分子基础和治疗干预的潜在靶点提供了见解。尽管PDB有在家族中聚集的倾向，但家庭成员中疾病严重程度的差异以及发病率的下降表明环境因素可能也在PDB的病理生理过程中起作用。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知之甚少。幸运的是，大多数PDB患者通过静脉输注氨基双膦酸盐（如唑来膦酸）可实现长期缓解。在本综述中，我们讨论了PDB的临床特征、遗传基础和最新研究进展等方面。
