2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) agonists have been shown to regulate bone development and remodeling in a species-, ligand-, and age-specific manner, however the underlying mechanisms remain poorly understood. In this study, we characterized the effect of 0.01-30 μg/kg TCDD on the femoral morphology of male and female juvenile mice orally gavaged every 4 days for 28 days and used RNA-Seq to investigate gene expression changes associated with the resultant phenotype. Micro-computed tomography revealed that TCDD dose-dependently increased trabecular bone volume fraction (BVF) 2.9- and 3.3-fold in male and female femurs, respectively. Decreased serum tartrate-resistant acid phosphatase (TRAP) levels, combined with a reduced osteoclast surface to bone surface ratio and repression of femoral proteases (cathepsin K, matrix metallopeptidase 13), suggests that TCDD impaired bone resorption. Increased osteoblast counts at the trabecular bone surface were consistent with a reciprocal reduction in the number of bone marrow adipocytes, suggesting AhR activation may direct mesenchymal stem cell differentiation towards osteoblasts rather than adipocytes. Notably, femoral expression of transmembrane glycoprotein NMB (Gpnmb; osteoactivin), a positive regulator of osteoblast differentiation and mineralization, was dose-dependently induced up to 18.8-fold by TCDD. Moreover, increased serum levels of 1,25-dihydroxyvitamin D were in accordance with the renal induction of 1α-hydroxylase Cyp27b1 and may contribute to impaired bone resorption. Collectively, the data suggest AhR activation tipped the bone remodeling balance towards bone formation, resulting in increased bone mass with reduced marrow adiposity.

Tetrandrine enhances the ubiquitination and degradation of Syk through an AhR-c-src-c-Cbl pathway and consequently inhibits osteoclastogenesis and bone destruction in arthritis

“…The findings that AhR agonists such as TCDD, Bap and DIM could inhibit osteoclastogenesis 19 – 21 and tetrandrine could activate AhR in T lymphocytes 9 implied that AhR might mediate the anti-osteoclastogenesis effect of tetrandrine. Data of the present study showed that tetrandrine was indeed able to activate AhR in the pre-osteoclasts as evidenced by increasing AhR nuclear import and the expression of CYP1A1, and the anti-osteoclastogenesis effect of either tetrandrine or DIM (a known AhR agonist) was largely diminished by the treatment of CH223191 or AhR siRNA.…”

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

“…Considering that the AhR antagonist 2’,4’,6-trimethoxyflavone or inhibition of kynurenine synthesis decreased stroke-associated damage, it is conceivable that the AhR plays a role in this condition [ 82 ]. Several studies demonstrate the role of the AhR and its ligands (e.g., TCDD and benzo[a]pyrene) on bone, although there are some response-specific differences reported in rodent models [ 83 , 84 , 85 , 86 , 87 ]. In AhR null mice, there is an increase in bone volume fraction and decreased bone turnover and effects of ligands are variable and age-dependent.…”

Aryl hydrocarbon receptor in mesenchymal stromal cells: new frontiers in AhR biology

“…On the other hand, AhR activation by TCDD decreases bone marrow adipogenesis. Bone density increased in both male and female mice following dioxin exposure, and regulatory proteins that signal for osteogenic differentiation and mineralization were also significantly upregulated [75]. Taken together, it is likely that AhR plays a role in osteogenesis, but that role has not been clearly defined.…”