Sex-specific gene expression and its effect on osteoclast maturation

Osteoclasts lie at the root of abnormal bone loss associated with osteoporosis. Osteoporosis primarily affects women and develops when estrogen, a negative regulator of osteoclast life cycle, plummets with menopause. In addition to the role of estrogen, the existence of inherent differences between male and female osteoclasts has been established. Our previous RNA sequencing data has revealed sex-specific gene expression in osteoclasts, which may result in variable cellular behavior as well as further explain a higher prevalence of osteoporosis in women. In our analyses, we found that female osteoclasts retain higher expression of the pro-inflammatory receptor, Tolllike receptor 4 (TLR4), relative to males after differentiation from a macrophage precursor. Activation of TLR4 by bacterial lipopolysaccharide (LPS) is supportive to osteoclast differentiation. We found that females respond to LPS more strongly than males by forming more and larger osteoclasts. Additionally, we found that female osteoclasts have a higher expression of gene, GALNT, which encodes a glycosyltransferase responsible for attaching N-acetylgalactosamine to serine/threonine residues. This sugar is later used as a substrate for sialylation. Our analysis found that terminal α2-3 sialylation is necessary for proper osteoclast differentiation and morphology, but removal of these specific sialic acids does not appear to more strongly impact one sex over the other. In this study, we bring light to variance in gene expression between male and female osteoclasts, which may in turn be useful in therapeutically modulating cell behavior as a strategy to protect against bone loss