Role of TGFβ Signaling in Maternal Ethanol-Induced Fetal Articular Cartilage Dysplasia and Adult Onset of Osteoarthritis in Male Rats

Abstract

Based on our previous findings that prenatal ethanol exposure in offspring increased susceptibility to adult osteoarthritis, this study aimed to further investigate the direct toxicity of ethanol on fetal articular cartilage development. Rat bone marrow-derived stroma cells were capsulated in alginate beads, incubated in a chondrogenic differentiation medium, and cultured for 4 weeks with ethanol treatment at concentrations of 0, 4, 20, and 100 mM. Pregnant rats were treated with ethanol (4 g/kg/day) from gestational days (GDs) 9 to 20. At GD20 and postnatal weeks 2, 6, and 12, 8 male offspring were sacrificed, and 8 male offspring rats of 8-weeks old in each group were treated with or without intraarticular injection of papain for 4 weeks to verify the susceptibility of adult osteoarthritis. Ethanol treatment resulted in poor differentiation of bone marrow-derived stroma cells to chondrocytes and suppressed the expression of the transforming growth factor-β (TGFβ)-smad2/3-Sox9 signaling pathway. In animal experiments, the shape of articular cartilage in the ethanol treatment group was more disordered than that of the control group, the matrix was not deep, and the cartilage was thin, which showed poor cartilage development. The TGFβ signaling pathway in the ethanol treatment group was persistently low at all time points. After intraarticular injection of papain, histological analyses, and the Mankin score revealed increased cartilage destruction in the ethanol treatment group. Ethanol caused articular cartilage dysplasia that was programmed in adulthood via a low-functional TGFβ signaling pathway, and the tolerance of this articular cartilage to external stimuli was significantly decreased.

The miR-200b-3p/ERG/PTHrP Axis Mediates the Inhibitory Effect of Ethanol on the Differentiation of Rat Fetal Chondrocytes into Articular Cartilage

“…Interestingly, in this study, we also found that PEE can cause dysplasia of articular cartilage, which shares a common tissue source with transitional cartilage. The theory that adult OA has intrauterine origin was rst proposed and proven by our previous research (Chen et al 2019a;Li et al 2020;Ni et al 2015a;Ni et al 2018;Ni et al 2015b;Pan et al 2016;Tie et al 2016a;Tie et al 2016b). In this study, we dynamically observed the effects of ethanol on articular cartilage development in fetuses at three time points: arthrogenesis (GD14), articular chondrogenesis (GD17) and just before birth (GD20).…”

Naringin and bone marrow mesenchymal stem cells repair articular cartilage defects in rabbit knees through the transforming growth factor‑β superfamily signaling pathway

“…TGF-β3 and SOX-9 are the main indicators of activation of the TGF-β superfamily of signaling pathways (32). SOX-9 is regulated and controlled by the TGF-β superfamily signaling pathway and serves as the main indicator of downstream signal transmission (33). Areas of positive staining for TGF-β3 in the groups without oral administration of naringin were relatively weak ( Fig.…”

Age-related histological changes in rat tibia

“…The tibias were sectioned sagittally at a thickness of 5 μm. Safranin O/fast green staining and hematoxylin-eosin (H&E) staining were performed by standard procedures [10]. The photo images of histology were captured using the Nikon NIS Elements BR light microscope (Nikon, Tokyo, Japan).…”