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Aryl hydrocarbon receptors in osteoclast lineage cells are a negative regulator of bone mass
Tai-yong Yu1, Wei-jun Pang2, Gong-she Yang2
1Division of Integrative Pathophysiology, Proteo-Science Center, Graduate School of Medicine, Ehime University, Ehime 791-0295, Japan; Laboratory of Epigenetic Skeletal Diseases, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Abstract:
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 AhR(RANKΔOc/ΔOc) (RANK(Cre/+);AhR(flox/flox)) mice. We observed enhanced bone mass together with decreased resorption in both male and female 12 and 24-week-old AhR(RANKΔOc/ΔOc) mice. Control mice treated with 3-methylcholanthrene (3MC), an AhR agonist, exhibited decreased bone mass and increased bone resorption, whereas AhR(CtskΔOc/ΔOc) (Ctsk(Cre/+);AhR(flox/flox)) mice injected with 3MC appeared to have a normal bone phenotype. In vitro, bone marrow-derived macrophages (BMDMs) from AhR(RANKΔOc/ΔOc) mice exhibited impaired osteoclastogenesis and repressed differentiation with downregulated expression of B lymphocyte-induced maturation protein 1 (Blimp1), and cytochrome P450 genes Cyp1b1 and Cyp1a2. 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.
Insights
Aryl hydrocarbon receptors (AhRs) regulate bone resorption. Inhibiting AhRs in osteoclast cells may offer new treatments for bone loss diseases linked to environmental pollutants.
Area of Science:
- Bone biology and metabolism
- Cellular mechanisms of bone remodeling
- Environmental toxicology and skeletal health
Background:
- Aryl hydrocarbon receptors (AhRs) are crucial in physiological and pathological processes.
- Previous studies suggest AhRs impact bone metabolism, but cellular mechanisms are unclear.
- Understanding AhR's role is vital for bone health, especially concerning environmental factors.
Purpose of the Study:
- To investigate the specific function of AhR in bone metabolism within osteoclast lineage cells.
- To elucidate the cellular and molecular mechanisms by which AhR influences bone resorption.
- To assess the therapeutic potential of targeting AhRs in bone diseases.
Main Methods:
- Utilized AhR(RANKΔOc/ΔOc) and AhR(CtskΔOc/ΔOc) genetically modified mouse models.
- Administered 3-methylcholanthrene (3MC), an AhR agonist, to control and experimental groups.
- Performed in vitro studies using bone marrow-derived macrophages (BMDMs) to assess osteoclastogenesis and gene expression.
Main Results:
- AhR(RANKΔOc/ΔOc) mice exhibited increased bone mass and decreased bone resorption.
- 3MC treatment in control mice led to decreased bone mass and increased resorption.
- In vitro, AhR deficiency in BMDMs impaired osteoclast differentiation and downregulated key genes (Blimp1, Cyp1b1, Cyp1a2).
Conclusions:
- AhR in osteoclast lineage cells is a significant regulator of bone resorption.
- Targeting AhRs in osteoclasts may be a viable strategy for treating bone loss.
- Further research is needed on AhR inhibitors for bone diseases associated with environmental pollutants.
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