Regulation of gap junction function and Connexin 43 expression by cytochrome P450 oxidoreductase (CYPOR)

Cytochrome P450 oxidoreductase (CYPOR) is a microsomal electron‐transferring enzyme, which provides electrons to various redox partners, such as cytochromes P450, heme oxygenase, cytochrome b 5 and squalene monooxygenase. Human patients with severe forms of a CYPOR mutation exhibit bone defects such as cranio‐ and humero‐radial synostoses and long bone fractures, identified as Antley‐Bixler‐like Syndrome. CYPOR knock‐down in multiple osteoblast cell lines decreased the expression of Connexin 43 (Cx43), which is known to play a critical role in bone formation, modeling, and remodeling as well as decreased Gap Junction Intercellular Communication and hemichannel activity. Promoter luciferase assays revealed that the decrease in expression of Cx43 in CYPOR knock‐down cells was due to transcriptional repression. Primary osteoblasts isolated from calvariae from bone‐specific Por gene knock‐down mice recapitulated the findings in the cell lines. The possibility of up‐regulating Cx43 by vitamin D3 and retinoic acid, which are CYPOR metabolites is being pursued. Furthermore, the role of CYPOR in cell migration is being investigated as Cx43 is implicated in this process. Our study provides new insights into the regulation of gap junction function by CYPOR and suggests that Cx43 may play an important role(s) in CYPOR‐mediated bone defects. Support: GM081568 to BSM and. RK and MAR by EY012085 and AQ‐1507 to J X Jiang