Beneficial roles of the AhR ligand FICZ on the regenerative potentials of BMSCs and primed cartilage templates

Abstract

FICZ/AhR axis might be a potential target to achieve optimal bone regeneration for both BMSCs and primed cartilage templates.

Aryl hydrocarbon receptor (AhR)-mediated signaling as a critical regulator of skeletal cell biology

“…Moreover, in vivo administration of FICZ increased bone formation rate and mineral apposition rate in WT mice (Yoshikawa et al 2021). Similarly, a recent report by Huang et al demonstrated that FICZ treatment promoted osteogenic differentiation of rat bone marrow stromal cells (Huang et al 2022). However, kynurenine (another endogenous AhR ligand) inhibited differentiation of BMSC-derived osteoblasts, reducing mineralized matrix production by these cells, and also decreased dynamic indices of bone mineralization activity (Refaey et al 2017).…”

“…MSCs constitute a heterogenous population of cells that can differentiate into several mesodermal cell lineages such as chondrocytes, adipocytes, and osteoblasts (Abney & Galipeau 2021). The AhR is strongly expressed in MSCs (Huang et al 2022), and many independent reports indicate that AhR-mediated signaling inhibits MSC proliferation (Zhou et al 2017, Jia et al 2021, Huang et al 2022. Human bone marrow MSC proliferation was inhibited by AhR ligand kynurenine and stimulated by AhR inhibitor SR1 in a concentration and time-dependent manner (Jia et al 2021); proliferation was also stimulated through siRNA-mediated knockdown of AhR expression, which protected against the inhibitory effects of kynurenine (Jia et al 2021).…”

“…The cigarette smoke toxicant BaP decreased the proliferation and self-renewal of rat MSCs, comparable to the reduced proliferation rate seen in MSCs isolated from human smokers as compared to non-smokers (Zhou et al 2017). However, some disagreement exists, as the AhR ligand FICZ did not affect rat bone marrow MSC proliferation (Huang et al 2022). Other cellular processes relating to cell survival are also affected by AhR signaling in MSC, for instance, kynurenine disrupted autophagy and promoted senescence in murine bone marrow stromal cell (BMSC) in an AhRdependent manner (Kondrikov et al 2020).…”

“…The AhR has been reported to play a role in cartilage development and subsequent bone growth. For example, AhR expression was suppressed in cartilage templates, but activation of AhR by the endogenous ligand FICZ positively promoted later processes of endochondral ossification (Huang et al 2022). Cedervall et al investigated how AhR acts in growth plate chondrocytes to regulate bone elongation, beginning with the finding that AhR was broadly expressed in the growth plate cartilage of human subjects and more highly expressed in hypertrophic as compared to resting chondrocytes (Cedervall et al 2015).…”

Hypoxia caused by unilateral nasal obstruction decreases mandibular density in rats through inhibition of Cyp1a1 expression

“…The oxidoreduction state is associated with bone remodeling and contributes to bone loss (e.g., osteoblasts apoptosis, osteoclast formation, and inhibits mineralization and osteogenesis) 17 . A recent study demonstrated that Cyp1a1 is involved in the regulation of the osteogenic metabolism of BMSCs 18 . Therefore, we investigated the effect of hypoxia on Cyp1a1 and the mechanism of hypoxia regulating BMSCs osteogenesis through Cyp1a1.…”