Role of mitogen-activated protein kinase in osteoblast differentiation

Fu-Hsiung Lin, Jessica B Chang, Brian E Brigman
Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society 2011, 29 (2): 204-10
Local control of osteoblast differentiation and bone formation is not well understood. We have previously seen biphasic effects on cell differentiation in response to the short- and long-term exposure to IL-1β in rat calvarial osteoblasts. To characterize the signaling pathway mechanisms regulating IL-1β biphasic effects, we examined the contribution of mitogen-activated protein kinase (MAPK) family. Cells were pretreated with specific inhibitors to extracellular signal-regulated kinase (ERK, PD98059), p38 (SB203580), and c-JUN N-terminal kinase (JNK, SP600125), then co-cultured with IL-1β for 2, 4, and 6 days. Cell differentiation was determined by measuring bone nodules after 10 days of culture. These inhibitors did not alter biphasic effects of IL-1β on cell differentiation. However, PD98059 and U2016, another inhibitor of ERK activation robustly increased osteoblast differentiation compared to vehicle-treated control in a time- and dose-dependent manner. PD98059 appears to stimulate alkaline phosphatase (ALP) activity to promote cell differentiation, where IL-1β appears to suppress it. Interestingly, continuous ERK inhibition with PD98059, after 2 and 4 days of IL-1β treatment, enhanced the IL-1β anabolic effect by increasing bone nodules formed. These observations provide a potential mechanism involving ERK pathway in osteoblasts differentiation and suggest that MAPK family may not directly regulate IL-1β biphasic effects.

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