title: Activation of c-Jun NH(2)-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor.
abstract: Bone morphogenetic protein 2 (BMP-2) plays a critical role in the differentiation of precursor cells and has been approved for clinical application to induce new bone formation. To date, unexpectedly high doses of recombinant BMP-2 have been required to induce bone healing in humans. Thus, enhancing cellular responsiveness to BMP-2 potentially has critically important clinical implications. BMP responsiveness may be modulated in part by cross-talk with other signaling pathways, including mitogen-activated protein kinases (MAPKs). c-Jun NH(2)-terminal kinase (JNK) is a MAPK that has been reported to be required for late-stage differentiation of preosteoblasts and BMP-2-induced differentiation of preosteoblasts and pleuripotent cells. In this study we determined that MC3T3-E1-clone 24 cells (MC-24) can be induced by BMP-2 to differentiate into mineralizing osteoblast cultures. Using this inducible system, we employed both JNK loss-of-function and gain-of-function reagents to make three key observations: (1) JNK is required for phosphorylation of Smad1 by BMP-2 and subsequent activation of Smad1 signaling and osteoblast differentiation, (2) JNK1, but not JNK2, is required for BMP-2-induced formation of mineralized nodules, and (3) JNK1 activation decreases binding of inhibitory Smad6 to the type I BMP receptor (BMPR-I) and reciprocally increases binding of Smad1, both observations that would increase responsiveness to BMP-2. Understanding this and other pathways that lead to increased cellular responsiveness to BMPs could greatly aid more cost-effective and safe clinical delivery of these important molecules.
authors.affiliation: Atlanta Veterans Affairs Medical Center and Department of Orthopaedics, Emory University School of Medicine, Decatur, GA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Liu
authors.forename: Manjula
authors.initials: M
authors.lastname: Viggeswarapu
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Zheng
authors.forename: Louisa
authors.initials: L
authors.lastname: Titus
authors.forename: Scott D
authors.initials: SD
authors.lastname: Boden
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051905:Smad6 Protein / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D055396:Bone Morphogenetic Protein 2; D051898:Smad1 Protein; D051905:Smad6 Protein; D048031:JNK Mitogen-Activated Protein Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I