Abstract
Low bone mineral density (BMD) is a risk factor for osteoporosis. Osteoporosis is more prevalent in females than in males. So far, the pathophysiological mechanisms underlying osteoporosis are unclear. Peripheral blood monocytes (PBMs) are precursors of bone-resorbing osteoclasts. This study aims to identify PBM-expressed proteins (genes) influencing hip BMD in humans. We utilized three independent study cohorts (N=34, 29, 40), including premenopausal Caucasians with discordant hip BMD. We studied PBM proteome-wide protein expression profiles in cohort 1 and identified 57 differentially expressed proteins (DEPs) between low vs. high BMD subjects. One protein gelsolin (GSN), after validation by Western blotting, was subject to follow-up. We compared GSN mRNA level in PBM between low vs. high BMD subjects in cohorts 2 and 3. We genotyped SNPs across GSN in 2286 unrelated Caucasians (cohort 4) and 1627 Chinese (cohort 5) and tested their association with hip BMD in females and males, respectively. We discovered and validated that GSN protein expression level in PBM was down-regulated 3.0-fold in low vs. high BMD subjects (P<0.05). Down-regulation of GSN in PBM in low BMD subjects was also observed at mRNA level in both cohort 2 and cohort 3. We identified that SNP rs767770 was significantly associated with hip BMD in female Caucasians (P=0.0003) only. Integrating analyses of the datasets at DNA, RNA, and protein levels from female Caucasians substantiated that GSN is highly significant for hip BMD (P=0.0001). We conclude that GSN is a significant gene influencing hip BMD in female Caucasians.