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Dikkopf-1 promotes matrix mineralization of osteoblasts by regulating Ca+-CAMK2A- CREB1 pathway

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Dickkopf-1 (DKK1) is a secreted protein that acts as an antagonistof the canonical WNT/β-catenin pathway, which regulatesosteoblast differentiation. However, the role of DKK1 on osteoblastdifferentiation has not yet been fully clarified. Here, weinvestigate the functional role of DKK1 on osteoblast differentiation. Primary osteoprogenitor cells were isolated from humanspinal bone tissues. To examine the role of DKK1 in osteoblastdifferentiation, we manipulated the expression of DKK1, andthe cells were differentiated into mature osteoblasts. DKK1 overexpressionin osteoprogenitor cells promoted matrix mineralizationof osteoblast differentiation but did not promote matrixmaturation. DKK1 increased Ca+ influx and activation of theCa+/calmodulin-dependent protein kinase II Alpha (CAMK2A)-cAMP response element-binding protein 1 (CREB1) and increasedtranslocation of p-CREB1 into the nucleus. In contrast, stable DKK1knockdown in human osteosarcoma cell line SaOS2 exhibitedreduced nuclear translocation of p-CREB1 and matrix mineralization. Overall, we suggest that manipulating DKK1 regulatesthe matrix mineralization of osteoblasts by Ca+-CAMK2A-CREB1,and DKK1 is a crucial gene for bone mineralization of osteoblasts.

Abstract

Dickkopf-1 (DKK1) is a secreted protein that acts as an antagonistof the canonical WNT/β-catenin pathway, which regulatesosteoblast differentiation. However, the role of DKK1 on osteoblastdifferentiation has not yet been fully clarified. Here, weinvestigate the functional role of DKK1 on osteoblast differentiation. Primary osteoprogenitor cells were isolated from humanspinal bone tissues. To examine the role of DKK1 in osteoblastdifferentiation, we manipulated the expression of DKK1, andthe cells were differentiated into mature osteoblasts. DKK1 overexpressionin osteoprogenitor cells promoted matrix mineralizationof osteoblast differentiation but did not promote matrixmaturation. DKK1 increased Ca+ influx and activation of theCa+/calmodulin-dependent protein kinase II Alpha (CAMK2A)-cAMP response element-binding protein 1 (CREB1) and increasedtranslocation of p-CREB1 into the nucleus. In contrast, stable DKK1knockdown in human osteosarcoma cell line SaOS2 exhibitedreduced nuclear translocation of p-CREB1 and matrix mineralization. Overall, we suggest that manipulating DKK1 regulatesthe matrix mineralization of osteoblasts by Ca+-CAMK2A-CREB1,and DKK1 is a crucial gene for bone mineralization of osteoblasts.

참고문헌 (36)

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