MAPK signaling has stage-dependent osteogenic effects on human adipose-derived stem cells in vitro

References

• Zuk PA, Zhu M, Mizuno H, Huang JI, Futrell WJ, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multi-lineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7:211–226.
   Google Scholar
• Dudas JR, Marra KG, Cooper GM, Penascino VM, Mooney MP, Jiang S, Rubin JP, Losee JE. The osteogenic potential of adipose-derived stem cells for the repair of rabbit calvarial defects. Ann Plast Surg 2006;56:543–548.
   PubMed Web of Science ®Google Scholar
• Hicok KC, Du Laney TV, Zhou YS, Halvorsen YD, Hitt DC, Cooper LF, Gimble JM. Human adipose-derived adult stem cells produce osteoid in vivo. Tissue Eng 2004;10:371–380.
   PubMedGoogle Scholar
• Peterson B, Zhang J, Iglesias R, Kabo M, Hedrick M, Benhaim P, Lieberman JR. Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue. Tissue Eng 2005;11:120–129.
   PubMedGoogle Scholar
• Yoon E, Dhar S, Chun DE, Gharibjanian NA, Evans GR. In vivo osteogenic potential of human adipose-derived stem cells/poly lactide-co-glycolic acid constructs for bone regeneration in a rat critical-sized calvarial defect model. Tissue Eng 2007;13:619–627.
   PubMedGoogle Scholar
• Ahn HH, Kim KS, Lee JH, Lee JY, Kim BS, Lee IW, Chun HJ, Kim JH, Lee HB, Kim MS. In vivo osteogenic differentiation of human adipose-derived stem cells in an injectable in situ-forming gel Scaffold. Tissue Eng Part A 2009; 15(7):1821–1832.
   Google Scholar
• Cowan CM, Shi YY, Aalami OO, Chou YF, Mari C, Thomas R, Quarto N, Contag CH, Wu B, Longaker MT. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol 2004;22:560–567.
   PubMed Web of Science ®Google Scholar
• Cui L, Liu B, Liu G, Zhang W, Cen L, Sun J, Yin S, Liu W, Cao Y. Repair of cranial bone defects with adipose derived stem cells and coral scaffold in a canine model. Biomaterials 2007;28:5477–5486.
   PubMed Web of Science ®Google Scholar
• Conejero JA, Lee JA, Parrett BM, Terry M, Wear-Maggitti K, Grant RT, Breitbart AS. Repair of palatal bone defects using osteogenically differentiated fat-derived stem cells. Plast Reconstr Surg 2006;117:857–863.
   PubMed Web of Science ®Google Scholar
• Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002;13:4279–4295.
   PubMed Web of Science ®Google Scholar
• Knippenberg M, Helder MN, Doulabi BZ, Semeins CM, Wuisman PI, Klein-Nulend J. Adipose tissue-derived mesenchymal stem cells acquire bone cell-like responsiveness to fluid shear stress on osteogenic stimulation. Tissue Eng 2005;11:1780–1788.
   PubMedGoogle Scholar
• Duque G, Rivas D. Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J Bone Miner Res 2007;22:1603–1611.
   PubMed Web of Science ®Google Scholar
• Malladi P, Xu Y, Chiou M, Giaccia AJ, Longaker MT. Effect of reduced oxygen tension on chondrogenesis and osteogenesis in adipose-derived mesenchymal cells. Am J Physiol Cell Physiol 2006;290:C1139–46.
   PubMed Web of Science ®Google Scholar
• Cowan CM, Aalami OO, Shi YY, Chou YF, Mari C, Thomas R, Quarto N, Nacamuli RP, Contag CH, Wu B, Longaker MT. Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover. Tissue Eng 2005;11:645–658.
   PubMedGoogle Scholar
• Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hedrick MH, Benhaim P. Bone induction by BMP-2 transduced stem cells derived from human fat. J Orthop Res 2003;21:622–629.
   PubMed Web of Science ®Google Scholar
• Daniels O. Guidelines for training in paediatric cardiology. Cardiol Young 2000;10:76–79.
   PubMed Web of Science ®Google Scholar
• Valentin-Opran A, Wozney J, Csimma C, Lilly L, Riedel GE. Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop Relat Res 2002;395:110–120.
   Google Scholar
• Woo EJ. Adverse events reported after the use of recombinant human bone morphogenetic protein 2. J Oral Maxillofac Surg 2012;70:765–767.
   PubMed Web of Science ®Google Scholar
• Chou Y-F, Zuk PA, Chang T-L, Benhaim P, Wu BM. Adipose-derived stem cells and BMP2: part 1 BMP2-treated adipose-derived stem cells do not improve repair of segmental femoral defects. Conn Tiss Res 2010; 52(2):109–118.
   Web of Science ®Google Scholar
• Zuk P, Chou YF, Mussano F, Benhaim P, Wu BM. Adipose-derived stem cells and BMP2: part 2. BMP2 may not influence the osteogenic fate of human adipose-derived stem cells. Connect Tissue Res 2011;52:119–132.
   PubMed Web of Science ®Google Scholar
• Gomez N, Cohen P. Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases. Nature 1991;353:170–173.
   PubMed Web of Science ®Google Scholar
• Guicheux J, Lemonnier J, Ghayor C, Suzuki A, Palmer G, Caverzasio J. Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. J Bone Miner Res 2003;18:2060–2068.
   PubMed Web of Science ®Google Scholar
• Lemonnier J, Ghayor C, Guicheux J, Caverzasio J. Protein kinase C-independent activation of protein kinase D is involved in BMP-2-induced activation of stress mitogen-activated protein kinases JNK and p38 and osteoblastic cell differentiation. J Biol Chem 2004;279:259–264.
   PubMed Web of Science ®Google Scholar
• Lou J, Tu Y, Li S, Manske PR. Involvement of ERK in BMP-2 induced osteoblastic differentiation of mesenchymal progenitor cell line C3H10T1/2. Biochem Biophys Res Commun 2000;268:757–762.
   PubMed Web of Science ®Google Scholar
• Gallea S, Lallemand F, Atfi A, Rawadi G, Ramez V, Spinella-Jaegle S, Kawai S, Faucheu C, Huet L, Baron R, Roman-Roman S. Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. Bone 2001;28:491–498.
   PubMed Web of Science ®Google Scholar
• Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002;298:1911–1912.
   PubMed Web of Science ®Google Scholar
• Kyosseva SV. Mitogen-activated protein kinase signaling. Int Rev Neurobiol 2004;59:201–220.
   PubMed Web of Science ®Google Scholar
• Higuchi C, Myoui A, Hashimoto N, Kuriyama K, Yoshioka K, Yoshikawa H, Itoh K. Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of the extracellular matrix. J Bone Miner Res 2002;17:1785–1794.
   PubMed Web of Science ®Google Scholar
• Hu Y, Chan E, Wang SX, Li B. Activation of p38 mitogen-activated protein kinase is required for osteoblast differentiation. Endocrinology 2003;144:2068–2074.
   PubMed Web of Science ®Google Scholar
• Huang Z, Cheng SL, Slatopolsky E. Sustained activation of the extracellular signal-regulated kinase pathway is required for extracellular calcium stimulation of human osteoblast proliferation. J Biol Chem 2001;276:21351–21358.
   PubMed Web of Science ®Google Scholar
• Jaiswal RK, Jaiswal N, Bruder SP, Mbalaviele G, Marshak DR, Pittenger MF. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J Biol Chem 2000;275:9645–9652.
   PubMed Web of Science ®Google Scholar
• Suzuki A, Guicheux J, Palmer G, Miura Y, Oiso Y, Bonjour JP, Caverzasio J. Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation. Bone 2002;30:91–98.
   PubMed Web of Science ®Google Scholar
• Chang J, Sonoyama W, Wang Z, Jin Q, Zhang C, Krebsbach PH, Giannobile W, Shi S, Wang CY. Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J Biol Chem 2007;282:30938–30948.
   PubMed Web of Science ®Google Scholar
• Rodriguez JP, Rios S, Fernandez M, Santibanez JF. Differential activation of ERK1,2 MAP kinase signaling pathway in mesenchymal stem cell from control and osteoporotic postmenopausal women. J Cell Biochem 2004;92:745–754.
   PubMed Web of Science ®Google Scholar
• Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.
   PubMed Web of Science ®Google Scholar
• Catalano MG, Marano F, Rinella L, De Girolamo L, Bosco O, Fortunati N, Berta L, Frairia R. Extracorporeal shockwaves (ESWs) enhance the osteogenic medium-induced differentiation of adipose-derived stem cells into osteoblast-like cells. J Tissue Eng Regen Med 2014; 11(12):390–399.
   Google Scholar
• Lu Z, Wang G, Dunstan CR, Chen Y, Lu WY, Davies B, Zreiqat H. Activation and promotion of adipose stem cells by tumour necrosis factor-alpha preconditioning for bone regeneration. J Cell Physiol 2013;228:1737–1744.
   PubMed Web of Science ®Google Scholar
• Monaco E, Bionaz M, Rodriguez-Zas S, Wl H, Wheeler MB. Transcriptomics comparison between porcine adipose and bone marrow mesenchymal stem cells during in vitro osteogenic and adipogenic differentiation. Plos One 2012;7:e32481.
   PubMed Web of Science ®Google Scholar
• Liu Q, Cen L, Zhou H, Yin S, Liu G, Liu W, Cao Y, Cui L. The role of the extracellular signal-related kinase signaling pathway in osteogenic differentiation of human adipose-derived stem cells and in adipogenic transition initiated by dexamethasone. Tissue Eng Part A 2009;15:3487–3497.
   PubMed Web of Science ®Google Scholar
• Pilgaard L, Lund P, Duroux M, Lockstone H, Taylor J, Emmersen J, Fink T, Ragoussis J, Zachar V. Transcriptional signature of human adipose tissue-derived stem cells (hASCs) preconditioned for chondrogenesis in hypoxic conditions. Exp Cell Res 2009;315:1937–1952.
   PubMed Web of Science ®Google Scholar
• Charoenpanich A, Wall ME, Tucker CJ, Andrews DM, Lalush DS, Loboa EG. Microarray analysis of human adipose-derived stem cells in three-dimensional collagen culture: osteogenesis inhibits bone morphogenic protein and Wnt signaling pathways, and cyclic tensile strain causes upregulation of proinflammatory cytokine regulators and angiogenic factors. Tissue Eng Part A 2011;17:2615–2627.
   PubMed Web of Science ®Google Scholar
• Zhu M, Heydarkhan-Hagvall S, Hedrick M, Benhaim P, Zuk P. Manual isolation of adipose-derived stem cells from human lipoaspirates. J Vis Exp 2015; 79:e50585.
   Google Scholar
• Chou YF, Dunn JC, Wu BM. In vitro response of MC3T3-E1 pre-osteoblasts within three-dimensional apatite-coated PLGA scaffolds. J Biomed Mater Res B Appl Biomater 2005;75:81–90.
   PubMed Web of Science ®Google Scholar
• Reffas S, Schlegel W. Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase mitogen-activated protein kinases (MKP)-3 and MKP-1 in differentiating P19 cells. Biochem J 2000;352 Pt 3:701–708.
   PubMedGoogle Scholar
• Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 1993;75:487–493.
   PubMed Web of Science ®Google Scholar
• Engelbrecht Y, De Wet H, Horsch K, Langeveldt CR, Hough FS, Hulley PA. Glucocorticoids induce rapid up-regulation of mitogen-activated protein kinase phosphatase-1 and dephosphorylation of extracellular signal-regulated kinase and impair proliferation in human and mouse osteoblast cell lines. Endocrinology 2003;144:412–422.
   PubMed Web of Science ®Google Scholar
• Johnson RB, Henderson JS. Enhancement by sodium orthovanadate of the formation and mineralization of bone nodules by chick osteoblasts in vitro. Arch Oral Biol 1997;42:271–276.
   PubMed Web of Science ®Google Scholar
• Chou YF, Chiou WA, Xu Y, Dunn JC, Wu BM. The effect of pH on the structural evolution of accelerated biomimetic apatite. Biomaterials 2004;25:5323–5331.
   PubMed Web of Science ®Google Scholar
• Schindeler A, Little DG. Ras-MAPK signaling in osteogenic differentiation: friend or foe? J Bone Miner Res 2006;21:1331–1338.
   PubMed Web of Science ®Google Scholar
• Greenblatt MB, Shim JH, Glimcher LH. Mitogen-activated protein kinase pathways in osteoblasts. Annu Rev Cell Dev Biol 2013;29:63–79.
   PubMed Web of Science ®Google Scholar
• Liu Y, Zheng WK, Gao WS, Shen Y, Ding WY. Function of TGF-beta and p38 MAKP signaling pathway in osteoblast differentiation from rat adipose-derived stem cells. Eur Rev Med Pharmacol Sci 2013;17:1611–1619.
   PubMed Web of Science ®Google Scholar
• Gu H, Huang Z, Yin X, Zhang J, Gong L, Chen J, Rong K, Xu J, Lu L, Cui L. Role of c-Jun N-terminal kinase in the osteogenic and adipogenic differentiation of human adipose-derived mesenchymal stem cells. Exp Cell Res 2015;339:112–121.
   PubMed Web of Science ®Google Scholar
• MacDonald DE, Betts F, Stranick M, Doty S, Boskey AL. Physicochemical study of plasma-sprayed hydroxyapatite-coated implants in humans. J Biomed Mater Res 2001;54:480–490.
   PubMed Web of Science ®Google Scholar
• Bonar LC, Shimizu M, Roberts JE, Griffin RG, Glimcher MJ. Structural and composition studies on the mineral of newly formed dental enamel: a chemical, x-ray diffraction, and 31P and proton nuclear magnetic resonance study. J Bone Miner Res 1991;6:1167–1176.
   PubMed Web of Science ®Google Scholar
• Querido W, Abracado LG, Rossi AL, Campos AP, Rossi AM, San Gil RA, Borojevic R, Balduino A, Farina M. Ultrastructural and mineral phase characterization of the bone-like matrix assembled in F-OST osteoblast cultures. Calcif Tissue Int 2011;89:358–371.
   PubMed Web of Science ®Google Scholar
• Rey C, Kim HM, Gerstenfeld L, Glimcher MJ. Structural and chemical characteristics and maturation of the calcium-phosphate crystals formed during the calcification of the organic matrix synthesized by chicken osteoblasts in cell culture. J Bone Miner Res 1995;10:1577–1588.
   PubMed Web of Science ®Google Scholar
• Hadzir SN, Ibrahim SN, Abdul Wahab RM, Zainol Abidin IZ, Senafi S, Ariffin ZZ, Abdul Razak M, Zainal Ariffin SH. Ascorbic acid induces osteoblast differentiation of human suspension mononuclear cells. Cytotherapy 2013;16:674–682.
   PubMed Web of Science ®Google Scholar
• Giachelli CM, Jono S, Shioi A, Nishizawa Y, Mori K, Morii H. Vascular calcification and inorganic phosphate. Am J Kidney Dis 2001;38:S34–7.
   PubMed Web of Science ®Google Scholar
• Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, Jahnen-Dechent W, Weissberg PL, Shanahan CM. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 2004;15:2857–2867.
   PubMed Web of Science ®Google Scholar
• Appleford MR, Oh S, Cole JA, Carnes DL, Lee M, Bumgardner JD, Haggard WO, Ong JL. Effects of trabecular calcium phosphate scaffolds on stress signaling in osteoblast precursor cells. Biomaterials 2007;28:2747–2753.
   PubMed Web of Science ®Google Scholar
• Suzuki A, Ghayor C, Guicheux J, Magne D, Quillard S, Kakita A, Ono Y, Miura Y, Oiso Y, Itoh M, Caverzasio J. Enhanced expression of the inorganic phosphate transporter Pit-1 is involved in BMP-2-induced matrix mineralization in osteoblast-like cells. J Bone Miner Res 2006;21:674–683.
   PubMed Web of Science ®Google Scholar
• Ge C, Xiao G, Jiang D, Franceschi RT. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J Cell Biol 2007;176:709–718.
   PubMed Web of Science ®Google Scholar
• Chen YJ, Kuo YR, Yang KD, Wang CJ, Sheen Chen SM, Huang HC, Yang YJ, Yi-Chih S, Wang FS. Activation of extracellular signal-regulated kinase (ERK) and p38 kinase in shock wave-promoted bone formation of segmental defect in rats. Bone 2004;34:466–477.
   PubMed Web of Science ®Google Scholar
• Fu L, Tang T, Miao Y, Zhang S, Qu Z, Dai K. Stimulation of osteogenic differentiation and inhibition of adipogenic differentiation in bone marrow stromal cells by alendronate via ERK and JNK activation. Bone 2008;43:40–47.
   PubMed Web of Science ®Google Scholar
• Yu Y, Mu J, Fan Z, Lei G, Yan M, Wang S, Tang C, Wang Z, Yu J, Zhang G. Insulin-like growth factor 1 enhances the proliferation and osteogenic differentiation of human periodontal ligament stem cells via ERK and JNK MAPK pathways. Histochem Cell Biol 2012;137:513–525.
   PubMed Web of Science ®Google Scholar
• Wang Y, Li J, Song W, Yu J. Mineral trioxide aggregate upregulates odonto/osteogenic capacity of bone marrow stromal cells from craniofacial bones via JNK and ERK MAPK signalling pathways. Cell Prolif 2014;47:241–248.
   PubMed Web of Science ®Google Scholar
• Chiu LH, Yeh TS, Huang HM, Leu SJ, Yang CB, Tsai YH. Diverse effects of type II collagen on osteogenic and adipogenic differentiation of mesenchymal stem cells. J Cell Physiol 2011;227:2412–2420.
   Web of Science ®Google Scholar
• Zhu M, Kohan E, Bradley J, Hedrick M, Benhaim P, Zuk P. The effect of age on osteogenic, adipogenic and proliferative potential of female adipose-derived stem cells. J Tissue Eng Regen Med 2009;3:290–301.
   PubMed Web of Science ®Google Scholar
• Kornicka K, Marycz K, Tomaszewski KA, Maredziak M, Smieszek A. The effect of age on osteogenic and adipogenic differentiation potential of human adipose derived stromal stem cells (hASCs) and the impact of stress factors in the course of the differentiation process. Oxid Med Cell Longev 2015;2015:309169.
   PubMed Web of Science ®Google Scholar
• Yang HJ, Kim KJ, Kim MK, Lee SJ, Ryu YH, Seo BF, Oh DY, Ahn ST, Lee HY, Rhie JW. The stem cell potential and multipotency of human adipose tissue-derived stem cells vary by cell donor and are different from those of other types of stem cells. Cells Tissues Organs 2014;199:373–383.
   PubMed Web of Science ®Google Scholar
• Aksu AE, Rubin JP, Dudas JR, Marra KG. Role of gender and anatomical region on induction of osteogenic differentiation of human adipose-derived stem cells. Ann Plast Surg 2008;60:306–322.
   PubMed Web of Science ®Google Scholar
• Levi B, James AW, Glotzbach JP, Wan DC, Commons GW, Longaker MT. Depot-specific variation in the osteogenic and adipogenic potential of human adipose-derived stromal cells. Plast Reconstr Surg 2010;126:822–834.
   PubMed Web of Science ®Google Scholar
• Iwen KA, Priewe AC, Winnefeld M, Rose C, Siemers F, Rohwedel J, Cakiroglu F, Lehnert H, Schepky A, Klein J, Kramer J. Gluteal and abdominal subcutaneous adipose tissue depots as stroma cell source: gluteal cells display increased adipogenic and osteogenic differentiation potentials. Exp Dermatol 2014;23:395–400.
   PubMed Web of Science ®Google Scholar
• Lasa M, Abraham SM, Boucheron C, Saklatvala J, Clark AR. Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Mol Cell Biol 2002;22:7802–7811.
   PubMed Web of Science ®Google Scholar
• Horsch K, De Wet H, Schuurmans MM, Allie-Reid F, Cato AC, Cunningham J, Burrin JM, Hough FS, Hulley PA. Mitogen-activated protein kinase phosphatase 1/dual specificity phosphatase 1 mediates glucocorticoid inhibition of osteoblast proliferation. Mol Endocrinol 2007;21:2929–2940.
   PubMed Web of Science ®Google Scholar
• Camps M, Nichols A, Arkinstall S. Dual specificity phosphatases: a gene family for control of MAP kinase function. Faseb J 2000;14:6–16.
   PubMed Web of Science ®Google Scholar
• Owens DM, Keyse SM. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 2007;26:3203–3213.
   PubMed Web of Science ®Google Scholar
• Phillips JE, Gersbach CA, Wojtowicz AM, Garcia AJ. Glucocorticoid-induced osteogenesis is negatively regulated by Runx2/Cbfa1 serine phosphorylation. J Cell Sci 2006;119:581–591.
   PubMed Web of Science ®Google Scholar
• Ge C, Xiao G, Jiang D, Yang Q, Hatch NE, Roca H, Franceschi RT. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J Biol Chem 2009;284:32533–32543.
   PubMed Web of Science ®Google Scholar
• Bai B, He J, Li YS, Wang XM, Ai HJ, Cui FZ. Activation of the ERK1/2 signaling pathway during the osteogenic differentiation of mesenchymal stem cells cultured on substrates modified with various chemical groups. Biomed Res Int 2013;2013:361906.
   PubMed Web of Science ®Google Scholar
• Nie J, Zhang B, Gu B, Liu N. Effects of p38 mitogen-activated protein kinase on osteogenic differentiation of human periodontal ligament stem cells in inflammatory microenvironment. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2015;37:1–7.
   PubMedGoogle Scholar
• Grammer TC, Blenis J. Evidence for MEK-independent pathways regulating the prolonged activation of the ERK-MAP kinases. Oncogene 1997;14:1635–1642.
   PubMed Web of Science ®Google Scholar
• Simard FA, Cloutier A, Ear T, Vardhan H. McDonald PP. MEK-independent ERK activation in human neutrophils and its impact on functional responses. J Leukoc Biol 2015;98:565–573.
   PubMed Web of Science ®Google Scholar
• Aksamitiene E, Kholodenko BN, Kolch W, Hoek JB, Kiyatkin A. PI3K/Akt-sensitive MEK-independent compensatory circuit of ERK activation in ER-positive PI3K-mutant T47D breast cancer cells. Cell Signal 2010;22:1369–1378.
   PubMed Web of Science ®Google Scholar
• Bruder SP, Gazit D, Passi-Even L, Bab I, Caplan AI. Osteochondral differentiation and the emergence of stage-specific osteogenic cell-surface molecules by bone marrow cells in diffusion chambers. Bone Miner 1990;11:141–151.
   PubMedGoogle Scholar
• Zhao YF, Xu J, Wang WJ, Wang J, He JW, Li L, Dong Q, Xiao Y, Duan XL, Yang X, Liang YW, Song T, Tang M, Zhao D, Luo JY. Activation of JNKs is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells. BMB Rep 2013;46:422–427.
   PubMed Web of Science ®Google Scholar
• Lai CF, Chaudhary L, Fausto A, Halstead LR, Ory DS, Avioli LV, Cheng SL. Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells. J Biol Chem 2001;276:14443–14450.
   PubMed Web of Science ®Google Scholar
• Sciandra M, Marino MT, Manara MC, Guerzoni C, Grano M, Oranger A, Lucarelli E, Lollini PL, Dozza B, Pratelli L, Renzo MF, Colombo MP, Picci P, Scotlandi K. CD99 drives terminal differentiation of osteosarcoma cells by acting as a spatial regulator of ERK 1/2. J Bone Miner Res 2014;29:1295–1309.
   PubMed Web of Science ®Google Scholar
• Novogrodsky A, Vanichkin A, Patya M, Gazit A, Osherov N, Levitzki A. Prevention of lipopolysaccharide-induced lethal toxicity by tyrosine kinase inhibitors. Science 1994;264:1319–1322.
   PubMed Web of Science ®Google Scholar
• Cotrim CZ, Amado FL, Helguero LA. Estrogenic effect of the MEK1 inhibitor PD98059 on endogenous estrogen receptor alpha and beta. J Steroid Biochem Mol Biol 2011;124:25–30.
   PubMed Web of Science ®Google Scholar
• Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science 2002;296:550–553.
   PubMed Web of Science ®Google Scholar
• McManus MT, Sharp PA. Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 2002;3:737–747.
   PubMed Web of Science ®Google Scholar
• Lee MJ, Chen HT, Ho ML, Chen CH, Chuang SC, Huang SC, Fu YC, Wang GJ, Kang L, Chang JK. PPARgamma silencing enhances osteogenic differentiation of human adipose-derived mesenchymal stem cells. J Cell Mol Med 2013;17:1188–1193.
   PubMed Web of Science ®Google Scholar
• Li CJ, Madhu V, Balian G, Dighe AS, Cui Q. Cross-talk between VEGF and BMP-6 pathways accelerates osteogenic differentiation of human adipose-derived stem cells. J Cell Physiol 2015;230:2671–2682.
   PubMed Web of Science ®Google Scholar
• Wang C, Lin K, Chang J, Sun J. Osteogenesis and angiogenesis induced by porous beta-CaSiO(3)/PDLGA composite scaffold via activation of AMPK/ERK1/2 and PI3K/Akt pathways. Biomaterials 2013;34:64–77.
   Google Scholar
• Jin Y, Zhang W, Liu Y, Zhang M, Xu L, Wu Q, Zhang X, Zhu Z, Huang Q, Jiang X. rhPDGF-BB via ERK pathway osteogenesis and adipogenesis balancing in ADSCs for critical-sized calvarial defect repair. Tissue Eng Part A 2014;20:3303–3313.
   PubMed Web of Science ®Google Scholar
• Wei J, Xu M, Zhang X, Meng S, Wang Y, Zhou T, Ma Q, Han B, Wei Y, Deng X. Enhanced osteogenic behavior of ADSCs produced by deproteinized antler cancellous bone and evidence for involvement of ERK signaling pathway. Tissue Eng Part A 2015;21:1810–1821.
   PubMed Web of Science ®Google Scholar
• Brown JC, Rosenquist TH, Monaghan DT. ERK2 activation by homocysteine in vascular smooth muscle cells. Biochem Biophys Res Commun 1998;251:669–676.
   PubMed Web of Science ®Google Scholar
• Park S, Kim H, Kim SJ. Stimulation of ERK2 by taurine with enhanced alkaline phosphatase activity and collagen synthesis in osteoblast-like UMR-106 cells. Biochem Pharmacol 2001;62:1107–1111.
   PubMed Web of Science ®Google Scholar