Genetics of osteoporosis: searching for candidate genes for bone fragility

ABSTRACT The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e.g. idiopathic juvenile and pregnancy-related osteoporosis), and, chiefly, genome-wide association studies (GWAS) in large populations. Altogether, these efforts have greatly increased the understanding of molecular mechanisms behind bone remodelling, which has rapidly translated into the development of novel therapeutic strategies, exemplified by the tales of cathepsin K (CTSK) and sclerostin (SOST). Additional biological evidence of involvement in bone physiology still lacks for several candidate genes arisen from GWAS, opening an opportunity for the discovery of new mechanisms regulating bone strength, particularly with the advent of high-throughput genomic technologies. In this review, candidate genes for bone fragility will be presented in comprehensive tables and discussed with regard to how their association with osteoporosis emerged, highlighting key players such as LRP5, WNT1 and PLS3. Current limitations in our understanding of the genetic contribution to osteoporosis, such as yet unidentified genetic modifiers, may be overcome in the near future with better genotypic and phenotypic characterisation of large populations and the detailed study of candidate genes in informative individuals with marked phenotype.

摘要：骨质疏松症（osteoporosis）是一种发病率与死亡率均较高的常见疾病，其发病机制涵盖环境与遗传两类因素。与其他复杂疾病类似，骨质疏松症的遗传基础一直难以明确。尽管如此，过去数十年间研究者已采用多种方法以鉴定骨脆性相关的候选基因，包括对具有显著骨表型的罕见单基因综合征开展研究（如成骨不全症（osteogenesis imperfecta）与骨硬化症（osteopetroses））、对具有极端骨质疏松表型的个体或家系进行分析（如特发性青少年骨质疏松症与妊娠相关性骨质疏松症），以及最主要的——在大群体中开展全基因组关联研究（genome-wide association studies, GWAS）。综上，这些研究极大地提升了我们对骨重塑（bone remodelling）分子机制的认知，并快速转化为新型治疗策略的开发，以组织蛋白酶K（cathepsin K, CTSK）与硬化蛋白（sclerostin, SOST）的研发应用为例。然而，从全基因组关联研究中筛选出的诸多候选基因，仍缺乏其参与骨生理过程的额外生物学证据，这为发现调控骨强度的新机制提供了契机，尤其随着高通量基因组技术的兴起。本综述将通过综合表格呈现骨脆性相关候选基因，并围绕其与骨质疏松症的关联是如何被发现展开讨论，重点介绍LRP5、WNT1及PLS3等关键基因。目前我们对骨质疏松症遗传贡献的认知仍存在局限，例如尚未明确的遗传修饰因子。未来通过对大群体进行更完善的基因型与表型特征分析，以及对表型特征显著的典型个体的候选基因展开深入研究，这些局限或将得以突破。