A road map for understanding molecular and genetic determinants of osteoporosis

Abstract

Osteoporosis is a highly prevalent disorder characterized by low bone mineral density and an increased risk of fracture, termed osteoporotic fracture. Notably, bone mineral density, osteoporosis and osteoporotic fracture are highly heritable; however, determining the genetic architecture, and especially the underlying genomic and molecular mechanisms, of osteoporosis in vivo in humans is still challenging. In addition to susceptibility loci identified in genome-wide association studies, advances in various omics technologies, including genomics, transcriptomics, epigenomics, proteomics and metabolomics, have all been applied to dissect the pathogenesis of osteoporosis. However, each technology individually cannot capture the entire view of the disease pathology and thus fails to comprehensively identify the underlying pathological molecular mechanisms, especially the regulatory and signalling mechanisms. A change to the status quo calls for integrative multi-omics and inter-omics analyses with approaches in 'systems genetics and genomics'. In this Review, we highlight findings from genome-wide association studies and studies using various omics technologies individually to identify mechanisms of osteoporosis. Furthermore, we summarize current studies of data integration to understand, diagnose and inform the treatment of osteoporosis. The integration of multiple technologies will provide a road map to illuminate the complex pathogenesis of osteoporosis, especially from molecular functional aspects, in vivo in humans.

Fig. 1 |. Prevalence of osteoporosis in populations of age 50 years and older in selected countries.

The prevalence of osteoporosis in the non-institutionalized USA population was calculated using data collected by the National Health and Nutrition Examination Survey 2005–2010 (REF.). The statistics for six European countries (France, Germany, Italy, Spain, Sweden and the UK) were retrieved from a report by the International Osteoporosis Foundation. The statistics for China and Korea were obtained from a meta-analysis study published in 2016 (REF.) and the Korea National Health and Nutrition Examination Survey 2008–2010 (REF.), respectively. Data for Canada, Japan and Australia were obtained from a 2014 study.

Fig. 2 |. Integrating multi-omics data to elucidate the molecular mechanisms of osteoporosis.

Multiple omics technologies, including genomics (mainly refers to genome-wide association studies (GWAS)), transcriptomics, epigenomics, proteomics and metabolomics, have been applied to dissect the pathogenesis of osteoporosis. Each technology individually can only provide limited insights into the biological mechanisms of osteoporosis. By integrating multiple omics data and following-up functional experiments in cell lines and/or animal models, researchers could capture a comprehensive view of the pathogenesis of this disorder.

Fig. 3 |. differentiation process of osteoblasts and osteoclasts.

Bone is a highly metabolically active tissue, which undergoes a continuous cycle of bone formation mediated by osteoblasts and bone resorption facilitated by osteoclasts. The cells that comprise bone tissue have diverse origins. Osteoblasts are derived from mesenchymal stem cells, which can also give rise to adipocytes, chondrocytes and myocytes. Osteoclasts are large, multinucleated cells formed by fusion of precursors derived from the monocyte–macrophage lineage. As the major cellular component of bone tissue, osteocytes originate from osteoblasts. We list several representative genes linked to bone metabolism by omics studies; functional experiments support their involvement in bone homeostasis. GWAS, genome-wide association studies; PTHR, parathyroid hormone receptor.