Searching for the Molecular Pathways Regulating Bone Mineral Density in the Proteome and RNA Interference Era

Abstract

Osteoporosis is a polygenic disorder associated with low bone mineral density and deterioration of bone microarchitecture with increased chance of bone fractures. Although bone matrix mineralization and osteoporosis are closely related, the mineralization of bone matrix is almost a forgotten aspect in osteoporosis research. The complex processes of bone matrix mineralization and bone remodeling are tightly regulated by several transcription factors and signal transduction pathways. However, signal transduction pathways occurring at a protein level that depends not only on mRNA transcriptional regulation but also on a multitude of translational and posttranslational controls. Furthermore, proteomics allow a discerning view of complex molecular pathways, provides an efficient method to determine protein candidates, and elucidates signal transduction pathways that regulate bone mineral density and accelerates the discovery of osteoporosis causative genes. RNA interference is a powerful tool for rapid analysis of gene functions. Therefore, strategies to combine proteomics with RNA interference and transgenic RNAi would greatly improve the efficiency of gene discovery and divulge the molecular pathways involved in osteoporosis pathophysiology. In this review, current methods employed to identify genes involved in osteoporosis, which include linkage analysis, candidate gene association studies, genome wide association studies, transcriptome microarray, and proteomics are evaluated, and a new strategy is proposed.

Novel insights into the complex architecture of osteoporosis molecular genetics

“…Bone remodeling, cyclic bone resorption and replacement by osteoclasts and osteoblasts, depends on orchestrated signaling pathways that elicit and preserve stable bone mass. However, signal transduction pathways occur at the protein level that depends on a plethora of regulated translational mechanisms, posttranslational modifications, and protein decay . Parathyroid hormone (PTH), core‐binding factor α‐1 (Cbfa1), Wnt/β‐catenin, the receptor activator of the nuclear factor kappa‐B (NF‐κB) ligand (RANKL), myostatin, and osteogenic exercise signaling pathways play central roles in the regulation of bone remodeling.…”