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We previously reported a novel interaction whereby MKs enhanced proliferation of osteoblast lineage\/osteoprogenitor cells (OBs) by a mechanism requiring direct cell\u2013cell contact. However, the signal transduction pathways and the downstream effector molecules involved in this process have not been characterized. Here we show that MKs contact with OBs, via beta1 integrin, activate the p38\/MAPKAPK2\/p90RSK kinase cascade in the bone cells, which causes Mdm2 to neutralizes p53\/Rb\u2010mediated check point and allows progression through the G1\/S. Interestingly, activation of MAPK (ERK1\/2) and AKT, collateral pathways that regulate the cell cycle, remained unchanged with MK stimulation of OBs. The MK\u2010to\u2010OB signaling ultimately results in significant increases in the expression of c\u2010fos and cyclin A, necessary for sustaining the OB proliferation. Overall, our findings show that OBs respond to the presence of MKs, in part, via an integrin\u2010mediated signaling mechanism, activating a novel response axis that de\u2010represses cell cycle activity. Understanding the mechanisms by which MKs enhance OB proliferation will facilitate the development of novel anabolic therapies to treat bone loss associated with osteoporosis and other bone\u2010related diseases. J. Cell. Physiol. 230: 578\u2013586, 2015. \u00a9 2014 Wiley Periodicals, Inc., A Wiley Company<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.24774","type":"journal-article","created":{"date-parts":[[2014,8,27]],"date-time":"2014-08-27T10:53:35Z","timestamp":1409136815000},"page":"578-586","source":"Crossref","is-referenced-by-count":16,"title":["Signaling Pathways Involved in Megakaryocyte\u2010Mediated Proliferation of Osteoblast Lineage Cells"],"prefix":"10.1002","volume":"230","author":[{"given":"Ying\u2010Hua","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Indiana University School of Medicine Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Drew A.","family":"Streicher","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Indiana University School of Medicine Indianapolis Indiana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David L.","family":"Waning","sequence":"additional","affiliation":[{"name":"Herman B. 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