Genetics of osteoporosis: accelerating pace in gene identification and validation

Abstract

Osteoporosis is characterized by low bone mineral density and structural deterioration of bone tissue, leading to an increased risk of fractures. It is the most common metabolic bone disorder worldwide, affecting one in three women and one in eight men over the age of 50. In the past 15 years, a large number of genes have been reported as being associated with osteoporosis. However, only in the past 4 years we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci. This increase in pace is mostly due to large-scale association studies, meta-analyses, and genome-wide association studies of both single nucleotide polymorphisms and copy number variations. A comprehensive review of these developments revealed that, to date, at least 15 genes (VDR, ESR1, ESR2, LRP5, LRP4, SOST, GRP177, OPG, RANK, RANKL, COLIA1, SPP1, ITGA1, SP7, and SOX6) can be reasonably assigned as confirmed osteoporosis susceptibility genes, whereas, another >30 genes are promising candidate genes. Notably, confirmed and promising genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/beta-catenin signaling pathway, and the RANKL/RANK/OPG pathway. New biological pathways will certainly emerge when more osteoporosis genes are identified and validated. These genetic findings may provide new routes toward improved therapeutic and preventive interventions of this complex disease.

Bone Overgrowth-associated Mutations in the LRP4 Gene Impair Sclerostin Facilitator Function

“…Finally, there are several examples, including the LRP5 and SOST gene, where the role of certain proteins in bone homeostasis was initially identified by the study of monogenic bone disorders (4,6,13,14), which was subsequently confirmed by genetic association studies illustrating that natural variants within these genes had an influence on BMD in the general population (54). Interestingly, a recent genome-wide association study of BMD in individuals of European descent has showed that non-synonymous SNPs in the LRP4 gene are asso-ciated, providing further support for a role of LRP4 in bone metabolism (55,56).…”

The genetic profile of bone repair

“…Such bone diseases and conditions include osteoporosis, osteoarthritis, heterotopic ossification (HO), Paget's disease, osteonecrosis of the femoral head (ONFH), and others. Extensive research on genetic variations and osteoporosis, has verified, to date, at least 15 genes including vita-min D receptor (VDR), lipoprotein receptor-related protein 5 (LRP5), sclerostin (SOST), osteoprotegerin (OPG), RANK/RANKL, and collagen type I alpha1 (COLIA1), as osteoporosis susceptibility genes, whereas, another >30 genes are promising candidate genes (23). Large genetic studies have also identified genetic variants within genes in signalling pathways involved in cartilage and bone biology, like the BMP pathway (e.g.…”

Functional relevance of the BMD-associated polymorphism rs312009: Novel Involvement of RUNX2 in LRP5 transcriptional regulation

“…However, regulatory involvement of RUNX2 in LRP5 transcription has not been reported to date. Several allelic variants in the LRP5 gene have been associated with osteoporotic phenotypes such as bone mineral density (BMD) and fracture in different association-analysis approaches, such as single missense single-nucleotide polymorphism (SNP) analysis, gene-wide analysis, and even genome-wide analysis (GWA; reviewed by Li and colleagues (28) ). Therefore LRP5 is a confirmed osteoporosis susceptibility gene.…”