Identification of novel genes and metabolites in bone metabolism using multiple omics approaches

Abstract

Osteoporosis is a growing public health problem worldwide. Due to the widening treatment gap among high fracture risk patients, the identification of effective and safe therapeutic targets for osteoporosis treatment has become a pressing need for disease management. In the present study, genomics and metabolomics studies were performed to identified novel gene(s)/metabolite(s) that regulate bone metabolism. Firstly, at gene level, genetic loci near AKAP11 have been identified by multiple genome-wide association studies of bone mineral density (BMD), but its function in bone remained unknown. Using genetically modified zebrafish and mouse models, AKAP11 was found to govern late osteoblast differentiation and mineralization. Exon sequencing of Southern Chinese cohort further demonstrated that rare damaging exonic mutations in AKAP11 were associated with low BMD in human. Secondly, as the metabolome is the manifestation of genetic and environmental interaction, a genome-metabolome-wide mendelian randomization analysis of BMD was performed. With the subsequent in vivo screening using zebrafish, a novel metabolite, 3-Methyl-2-oxovalerate (KMV) was identified to casually affect BMD. Additionally, mouse model mimicking post-menopausal bone loss shown consistent beneficial effect on bone metabolism with oral KMV supplementation. Further in vitro investigation revealed the dose dependent inhibitory effect of KMV on osteoclastogenesis. These findings demonstrated that KMV may protect against postmenopausal bone loss in human by reducing bone resorption. In conclusion, the present study has demonstrated by using genomic and metabolomic approaches, together with in vivo, in vitro screening and functional validation pipelines, novel gene (AKAP11) and metabolite (KMV) regulating bone metabolism were identified.