TRPV4 is involved in progesterone-mediated sexual dimorphism in mesenchymal stem cell functions and bio-mineralization

The prevalence of bone disorders in female has been linked with imbalances in sex hormones, especially during pregnancy and menopause. Apart from regulation of transcription, recent reports suggest the involvement of various ion channels which can also be the molecular targets of an array of steroids (and steroid-like molecules). The differences in steroid responses between males and females also impose the need to understand the complexity of steroid actions. This current in vitro study has been carried out during the osteoblast differentiation (day 1 and day 12, early and late time points respectively) using MSCs-derived from male and female animals and in the presence of progesterone (P4) and/or TRPV4 modulators to explore the existence of sexual dimorphism at the cellular level if any and possible involvement of TRPV4 and P4 in it. Different subcellular parameters such as cytosolic Ca²⁺, mitochondrial potential, cytosolic- and mitochondrial-ROS and functional assays such as bio-mineralization (BM) were performed. All these results point out that P4 modulates TRPV4 both in the short-term and long-term, but differently in male and female-derived primary cells. It is observed that P4 can modulate TRPV4 in a long-term, both transcription-dependent and transcription-independent manner. Thus, the observed sexual dimorphism at the cultured cellular system is more prominent in the early time point which seems to be dampened, but still exists in the later time points. These findings may be relevant for bone disorders due to hormonal imbalance.