Principal Investigator: Fei-Yan Deng, Ph.D.
Research Assistant: Yong Zeng
Research Assistant: Wei Zhu
Proteins are the major executors of the functions of genes. Osteoporosis, characterized by low bone mineral density (BMD), is a complex disease and has strong genetic determination. Genes influencing BMD variation and contributing to the development of osteoporosis in humans are largely unknown. The major purpose of our proteomics studies is to identify and characterize proteins and post-translational modifications related to bone phenotypes, with a goal to dissect genetic basis and elucidate pathophysiological mechanisms of osteoporosis.
The studies are to identify proteins (thus genes) that are differentially expressed in osteogenic cells in vivo in subjects with low vs. high BMD. Proteins significant for BMD variation are subjected to validation and downstream functional characterization.
In postmenopausal women in Chinese, we have identified and validated five proteins (RSU1, GSN, GSN, GPX1, and SOD2) expressed in circulating monocyte (CMs, i.e., potential precursors of bone-resorbing osteoclasts) and associated with low BMD. Based on functional evidences, we proposed a pathophysiological mechanism for osteoporosis (Figure 1).
In postmenopausal women in Caucasians, we discovered and validated a novel protein, Anxa2, which is expressed in CMs and associated with BMD variation. Follow-up in vitro functional study demonstrated that the Anxa2 protein, probably via stimulating monocyte migration from blood to bone, promotes osteoclast differentiation and bone resorption, and contributes to osteoporosis in humans.
Further studies are underway to identify gender-specific proteins contributing to pathogenesis of osteoporosis.
Beside changes in protein expression levels, post-translational modifications, e.g., protein phosphorylation, play fundamental roles in regulating various cellular processes. Protein phosphorylation is involved in regulation of protein conformation, protein interaction, protein localization, enzyme activity, etc. Abnormal regulation of protein phosphorylation has been found related to pathogenesis of diseases, such as cancer, Alzheimer's disease, etc.
To understand the roles of protein phosphorylation in the pathogenesis of osteoporosis, this study is attempted to identify phosphorylated proteins and specific phosphorylation sites, through qualitative and quantitative analyses of bone-related cells and tissues.
PhosSNPs are non-synonymous single nucleotide polymorphisms, which effect on protein functioning, via modifying protein phosphorylation. The study purpose is to identify phosSNPs important for bone phenotypes, and to characterize their functional mechanisms.
We identified a phosSNP rs6265 that was associated with BMD in Caucasians. Rs6265, probably via interacting with kinase CHEK2 and influencing phosphorylation status of bdnf protein and its functioning, contributes to BMD variation in humans. Molecular and cellular studies are underway to elucidate its functions and potential mechanisms.