Regulation of differentiation of hard-tissue-constituting cells by pH regulating proteins. Clarification of the mechanism and its application for regenerative medicine.

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We found that carbonic anhydrase-9 (CA9) is expressed in mouse chondrocytes and monocarboxylate transporter-1 (MCT1) in osteoblasts, respectively. Hence we investigated the roles of CA9 and MCT1 in differentiation of chondrocytes and osteoblasts, respectively. CA9 was expressed in proliferating but not in hypertrophic chondrocytes in the growth plates of mice. Suppression of CA9 expression by its siRNA induced the hypertrophic differentiation in mouse primary chondrocytes, indicating that CA9 has a role to suppress hypertrophic differentiation of chondrocytes. Suppression of the expression of MCT1 in mouse osteoblasts induced lowered expression of alkaline phosphatase (ALP), while lactate, an MCT1 substrate, augmented the expression of ALP in osteoblasts. We also found that MCT1 positively regulates phosphorylation and nuclear translocation of Smad1/5/8 in osteoblasts after stimulation by bone morphogenetic protein-2.