The Functional Roles of Mst1/2 in Bone Development and Homeostasis
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摘要Mst1/2, key membersof Hippo signalingpathway, play important roles in controllingcell proliferation and differentiation.However, the functional roles of Mst1/2 in bone developmentand homeostasisremain elusive.Here,we generatedtwo bone specificconditionalknockout mouse models in which Mst1/2 kinases weregenetically removed duringearly and matureosteoblasts differentiation respectively. We demonstrate that mice deficient of Mst1/2in early or mature osteoblasts both exhibit decreased bonemass accrual. The loss of bone mass accrual were attributed to bothbone formation and bone resorption processes. We showedthat Mst1/2 deficiency inhibit bone formation through attenuating osteoblast differentiation and mineralizationwithout affecting osteoblast proliferation.Surprisingly, osteoclast formation and differentiation ofMst1/2 mutant mice werealso inhibitedbothin vivoand in vitroas shown by significant reduction of RANKL to OPG ratio.Mechanistically, we found that Mst1/2inhibit AMPK activity and thusantagonizing Runx2 degradation to promote osteoblast differentiation. Moreover, Mst1/2 govern bone resorption by promoting PTHrP expression. In summary, our results demonstrate that Mst1/2 play positive role in regulating bone development and homeostasis through regulating AMPK activityand PTHrP expressionrespectively. Our findingsprovide new insightsfor future development of therapeutic strategy for skeletal diseases
著者Li Wenling, Mak Kingston
會議名稱Gordon Research Conference
會議地點New London, NH

上次更新時間 2018-18-01 於 08:22