Watts Laura M, Sparkes Penny C, Dewhurst Hannah F, Guilfoyle Siobhan E, Pollard Andrea S, Komla-Ebri Davide, Butterfield Natalie C, Williams Graham R, Bassett J H Duncan
Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
Bone. 2025 Jun;195:117472. doi: 10.1016/j.bone.2025.117472. Epub 2025 Mar 24.
Bone mineral density (BMD) and height are highly heritable traits for which hundreds of genetic loci have been linked through genome wide association studies (GWAS). FUBP3 is a DNA and RNA binding protein best characterised as a transcriptional regulator of c-Myc, but little is known about its role in vivo. Single nucleotide polymorphisms in FUBP3 at the 9q34.11 locus have been associated with BMD, fracture and height in multiple GWAS, but FUBP3 has no previously established role in the skeleton. We analysed Fubp3-deficient mice to determine the consequence of FUBP3 deficiency in vivo. Mice lacking Fubp3 had reduced survival to adulthood and impaired skeletal growth. Bone mass was decreased, most strikingly in the vertebrae, with altered trabecular micro-architecture. Fubp3 deficient bones were also weak. These data provide the first functional demonstration that Fubp3 is required for normal skeletal growth and development and maintenance of adult bone structure and strength, indicating that FUBP3 contributes to the GWAS association of 9q34.11 with variation in height, BMD and fracture.
骨矿物质密度（BMD）和身高是高度可遗传的性状，通过全基因组关联研究（GWAS）已将数百个基因位点与之联系起来。FUBP3是一种DNA和RNA结合蛋白，最典型的特征是作为c-Myc的转录调节因子，但对其在体内的作用知之甚少。在多个GWAS中，位于9q34.11位点的FUBP3单核苷酸多态性与BMD、骨折和身高相关，但FUBP3此前在骨骼中尚未确立作用。我们分析了Fubp3基因缺失的小鼠，以确定FUBP3缺乏在体内的后果。缺乏Fubp3的小鼠成年后的存活率降低，骨骼生长受损。骨量减少，最明显的是在椎骨，小梁微结构改变。Fubp3基因缺失的骨骼也很脆弱。这些数据首次提供了功能性证据，表明Fubp3是正常骨骼生长发育以及维持成年骨结构和强度所必需的，这表明FUBP3促成了9q34.11与身高、BMD和骨折变异的GWAS关联。
