Attenuated Monocyte Apoptosis, a New Mechanism for Osteoporosis Suggested by a Transcriptome-Wide Expression Study of Monocytes

BACKGROUND: Osteoporosis is caused by excessive bone resorption (by osteoclasts) over bone formation (by osteoblasts). Monocytes are important to osteoporosis by serving as progenitors of osteoclasts and produce cytokines for osteoclastogenesis. AIM: To identify osteoporosis-related genes, we performed microarray analyses of monocytes using Affymetrix 1.0 ST arrays in 42 (including 16 pre- and 26 postmenopausal) high hip BMD (bone mineral density) vs. 31 (including 15 pre- and 16 postmenopausal) low hip BMD Caucasian female subjects. Here, high vs. low BMD is defined as belonging to top vs. bottom 30% of BMD values in population. METHOD: Differential gene expression analysis in high vs. low BMD subjects was conducted in the total cohort as well as pre- and post-menopausal subjects. Focusing on the top differentially expressed genes identified in the total, the pre- and the postmenopausal subjects (with a p <5E-03), we performed replication of the findings in 3 independent datasets of microarray analyses of monocytes (total N = 125). RESULTS: We identified (in the 73 subjects) and successfully replicated in all the 3 independent datasets 2 genes, DAXX and PLK3. Interestingly, both genes are apoptosis induction genes and both down-regulated in the low BMD subjects. Moreover, using the top 200 genes identified in the meta-analysis across all of the 4 microarray datasets, GO term enrichment analysis identified a number of terms related to induction of apoptosis, for which the majority of component genes are also down-regulated in the low BMD subjects. Overall, our result may suggest that there might be a decreased apoptosis activity of monocytes in the low BMD subjects. CONCLUSION: Our study for the first time suggested a decreased apoptosis rate (hence an increased survival) of monocytes, an important osteoclastogenic cell, as a novel mechanism for osteoporosis.