Transgenic Mice with a Constitutively Active Aryl Hydrocarbon Receptor Display a Gender-Specific Bone Phenotype

Abstract

Bone tissue homeostasis is governed by hormones, growth factors, and cytokines and can be distorted by environmental pollutants, such as ligands to the aryl hydrocarbon receptor (AhR). A transgenic mouse expressing a constitutively active aryl hydrocarbon receptor (CA-AhR), mimicking continuous low-dose exposure to AhR ligands, was used to explore potential long-term effects of these ligands on bone. The density, content, and dimensions of cortical and trabecular bone, as well as physical properties, were significantly altered in female transgenic mice, while almost no alterations were detected in males. Osteoclast volume density and serum level of C-telopeptide of type I collagen (CTX), reflecting osteoclast activity, were both increased by approximately 60% in female CA-AhR mice, while serum tartrate-resistant acid phosphatase (TRAP) 5b, reflecting osteoclast numbers, was unchanged. Subsequently, the resorption index (CTX/TRAP 5b) was increased by 90%, indicating increased osteoclast activity in female CA-AhR. Moreover, the protein level of the osteoclast collagenase cathepsin K was increased by 40% in bone extracts of female CA-AhR mice. The messenger RNA expression of several osteoclast- and osteoblast-associated genes was altered in female transgenic mice but not in males. Notably, early markers for osteoclast and osteoblast differentiation were normal, while the expression of functional markers of osteoclasts and osteoblasts were reduced. In conclusion, a low continuous activation of the AhR leads to a skeletal phenotype with increased bone resorption associated with more ductile bones in females but not in males. The results indicate the presence of an interaction between the AhR and a female-specific mechanism implicated in inhibition of osteoclast development and function. Female bone tissue appears more susceptible to dioxins and other AhR ligands than male bone tissue.

Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes

“…2E). These findings are opposite to what is seen in female Ahr −/− mice (19). Ahr activation leads to the induction of a number of genes regulating metabolism, most specifically genes encoding the Cyp1 enzymes.…”

3,3′-Diindolylmethane increases bone mass by suppressing osteoclastic bone resorption in mice

“…Our laboratory, and other groups that have more recently evaluated systemic AhR KO mice, have found that bone mass increased, and bone resorption (as assessed by N.Oc/B.Pm and Oc.S/BS) decreased, as a result of the aryl hydrocarbon receptordeficiency in AhR KO mice (5,6). On the other hand, using transgenic mice expressing constitutively active AhR, Wejheden C et al found that bone mass decreased in conjunction with an increase in bone resorption markers, which included protein levels of the osteoclast collagenase cathepsin K and serum level of C-telopeptide of type I collagen (CTX), in female transgenic mice (36). These data showed that AhR decreased bone mass by increasing bone resorption in vivo, and suggested that selective inhibition of the AhR pathway may increase bone mass through suppression of osteoclastic bone resorption.…”

The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis

“…Moreover, c-Fos is required for the downstream induction of NFAT, cytoplasmic, calcineurin-dependent 1 (NFATc1) and fos-like Ag 1 (7,10). AhR 2/2 mice with systemic or osteoclast-specific deficiencies in AhR expression exhibit increased bone mass with decreased bone resorption (11)(12)(13), and bone resorption increases in mice overexpressing constitutively activated AhR (14). Evidence indicates that AhR is a positive regulator of osteoclastogenesis in vitro (11,12) and that AhR may mediate various activities of myeloid-lineage cells.…”