Aryl Hydrocarbon Receptors in Osteoclast Lineage Cells Are a Negative Regulator of Bone Mass

Abstract

<div><p>Aryl hydrocarbon receptors (AhRs) play a critical role in various pathological and physiological processes. Although recent research has identified AhRs as a key contributor to bone metabolism following studies in systemic AhR knockout (KO) or transgenic mice, the cellular and molecular mechanism(s) in this process remain unclear. In this study, we explored the function of AhR in bone metabolism using <i>AhR^{RANKΔOc/ΔOc}</i> (<i>RANK^Cre/+;AhR^flox/flox</i>) mice. We observed enhanced bone mass together with decreased resorption in both male and female 12 and 24-week-old <i>AhR^{RANKΔOc/ΔOc}</i> mice. Control mice treated with 3-methylcholanthrene (3MC), an AhR agonist, exhibited decreased bone mass and increased bone resorption, whereas <i>AhR^{CtskΔOc/ΔOc}</i> (<i>Ctsk^Cre/+;AhR^flox/flox</i>) mice injected with 3MC appeared to have a normal bone phenotype. <i>In vitro</i>, bone marrow-derived macrophages (BMDMs) from <i>AhR^{RANKΔOc/ΔOc}</i> mice exhibited impaired osteoclastogenesis and repressed differentiation with downregulated expression of B lymphocyte-induced maturation protein 1 (<i>Blimp1</i>), and cytochrome P450 genes <i>Cyp1b1</i> and <i>Cyp1a2</i>. Collectively, our results not only demonstrated that AhR in osteoclast lineage cells is a physiologically relevant regulator of bone resorption, but also highlighted the need for further studies on the skeletal actions of AhR inhibitors in osteoclast lineage cells commonly associated with bone diseases, especially diseases linked to environmental pollutants known to induce bone loss.</p></div