All-trans retinoic acid restored the osteogenic ability of BMP9 in osteosarcoma through the p38 MAPK pathway.

Osteosarcoma (OS) is the most common malignant bone tumour and is considered to be a disease caused by a dysfunction in differentiation. Bone morphogenetic protein 9 (BMP9) is the most potent osteogenic factor in mesenchymal stem cells, but it cannot induce osteogenic differentiation in OS cells; this might be one of the determinants in the pathogenesis of OS. All-trans retinoic acid (ATRA) can induce osteogenic differentiation of OS cells and potentiate BMP9-induced osteogenesis in preadipocytes. However, the concomitant effect of ATRA and BMP9 in OS cells is unclear; therefore, in the present study, we focused on this topic. The results showed that BMP9 significantly promoted the proliferation of human OS 143B cells and did not induce osteogenic differentiation of cells in vitro (p<0.01). ATRA inhibited proliferation and induced osteogenesis in 143B cells; these effects could be enhanced by BMP9 overexpression (p<0.05). ATRA could significantly increase the level of phosphorylated p38 MAPK (p-p38) in 143B cells, while BMP9 did not have any significant effect. Notably, BMP9 overexpression enhanced the ability of ATRA to increase the levels of p-p38. Both the osteogenic differentiation and the anti-proliferative activity of BMP9 in the presence of ATRA decreased upon treatment with a specific inhibitor of p38 MAPK (SB203580) (p<0.01). This study indicates that the osteogenic differentiation ability of BMP9 in 143B cells can be restored by ATRA, and the combination of BMP9 and ATRA generated a stronger anti-proliferative effect on 143B cells than ATRA alone. This result may be due to the activation of the p38 MAPK pathway.

[1]  Ming Yan,et al.  Insulin-like growth factor 1 promotes the proliferation and committed differentiation of human dental pulp stem cells through MAPK pathways. , 2016, Archives of oral biology.

[2]  Xiaofeng Wang,et al.  Microcystin-LR promotes cell proliferation in the mice liver by activating Akt and p38/ERK/JNK cascades. , 2016, Chemosphere.

[3]  W. Li,et al.  The E3 ubiquitin protein ligase MDM2 dictates all-trans retinoic acid-induced osteoblastic differentiation of osteosarcoma cells by modulating the degradation of RARα , 2016, Oncogene.

[4]  J. Dickinson,et al.  Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo , 2016, Oncotarget.

[5]  Jiaoti Huang,et al.  All-trans retinoic acids induce differentiation and sensitize a radioresistant breast cancer cells to chemotherapy , 2016, BMC Complementary and Alternative Medicine.

[6]  Shun-Fa Yang,et al.  Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways , 2016, Oncotarget.

[7]  Pu Zhang,et al.  BMP9/p38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer. , 2016, Oncology reports.

[8]  S. van den Heuvel,et al.  Coordinating cell proliferation and differentiation: Antagonism between cell cycle regulators and cell type-specific gene expression , 2016, Cell cycle.

[9]  N. Neophytou,et al.  Transcriptional Profiling Identifies the Signaling Axes of IGF and Transforming Growth Factor-β as Involved in the Pathogenesis of Osteosarcoma , 2016, Clinical orthopaedics and related research.

[10]  D. Spitz,et al.  Redox balance influences differentiation status of neuroblastoma in the presence of all-trans retinoic acid , 2015, Redox biology.

[11]  Maryam K. Mohammed,et al.  The Calcium-Binding Protein S100A6 Accelerates Human Osteosarcoma Growth by Promoting Cell Proliferation and Inhibiting Osteogenic Differentiation , 2015, Cellular Physiology and Biochemistry.

[12]  P. Knaus,et al.  Bone morphogenetic protein signaling in bone homeostasis. , 2015, Bone.

[13]  Yang Liu,et al.  Evodiamine inhibits the proliferation of human osteosarcoma cells by blocking PI3K/Akt signaling. , 2015, Oncology reports.

[14]  P. Meltzer,et al.  Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  R. Wu,et al.  Inactivation of the Phosphatidylinositol 3‐Kinase/Akt Pathway is Involved in BMP9‐mediated Tumor‐suppressive Effects in Gastric Cancer Cells , 2015, Journal of cellular biochemistry.

[16]  K. S. Hall,et al.  EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment† , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[17]  Xing Wang,et al.  The role of COX-2 in mediating the effect of PTEN on BMP9 induced osteogenic differentiation in mouse embryonic fibroblasts. , 2014, Biomaterials.

[18]  A. Bazhin,et al.  Knockdown of lecithin retinol acyltransferase increases all‐trans retinoic acid levels and restores retinoid sensitivity in malignant melanoma cells , 2014, Experimental dermatology.

[19]  Q. Shi,et al.  Bone Morphogenetic Protein-9 Induces PDLSCs Osteogenic Differentiation through the ERK and p38 Signal Pathways , 2014, International journal of medical sciences.

[20]  T. He,et al.  Bone morphogenetic protein-9 effectively induces osteo/odontoblastic differentiation of the reversibly immortalized stem cells of dental apical papilla. , 2014, Stem cells and development.

[21]  Ning Zhang,et al.  E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα , 2014, Cell cycle.

[22]  S. Dooley,et al.  Potential Roles of Bone Morphogenetic Protein (BMP)-9 in Human Liver Diseases , 2014, International journal of molecular sciences.

[23]  N. Katsanis,et al.  Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  T. He,et al.  Targeting BMP9-promoted human osteosarcoma growth by inactivation of notch signaling. , 2014, Current cancer drug targets.

[25]  Yang Liu,et al.  All-trans retinoic acid modulates bone morphogenic protein 9-induced osteogenesis and adipogenesis of preadipocytes through BMP/Smad and Wnt/β-catenin signaling pathways. , 2014, The international journal of biochemistry & cell biology.

[26]  Q. Shi,et al.  Bone morphogenetic protein 9 regulates tumor growth of osteosarcoma cells through the Wnt/β-catenin pathway. , 2014, Oncology reports.

[27]  Yang Liu,et al.  BMP9 and COX-2 form an important regulatory loop in BMP9-induced osteogenic differentiation of mesenchymal stem cells. , 2013, Bone.

[28]  G. Inman,et al.  BMP9 Is a Proliferative and Survival Factor for Human Hepatocellular Carcinoma Cells , 2013, PloS one.

[29]  B. He,et al.  P38 and ERK1/2 MAPKs Act in Opposition to Regulate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells , 2012, PloS one.

[30]  Jin Wang,et al.  Smads, p38 and ERK1/2 are involved in BMP9-induced osteogenic differentiation of C3H10T1/2 mesenchymal stem cells. , 2012, BMB reports.

[31]  L. Yin,et al.  BMP9-Induced Osteogenetic Differentiation and Bone Formation of Muscle-Derived Stem Cells , 2012, Journal of biomedicine & biotechnology.

[32]  R. Jha,et al.  Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing’s sarcoma , 2011, Medical science monitor : international medical journal of experimental and clinical research.

[33]  A. Ziemienowicz,et al.  Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation. , 2011, Annals of botany.

[34]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[35]  A. Cuadrado,et al.  Mechanisms and functions of p38 MAPK signalling. , 2010, The Biochemical journal.

[36]  T. He,et al.  Retinoic Acids Potentiate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells , 2010, PloS one.

[37]  Ximing J. Yang,et al.  Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells , 2010, Oncogene.

[38]  T. He,et al.  Synergistic Antitumor Effect of the Activated PPARγ and Retinoid Receptors on Human Osteosarcoma , 2010, Clinical Cancer Research.

[39]  G. Inman,et al.  Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/Smad4 to promote ovarian cancer cell proliferation. , 2009, Cancer research.

[40]  T. He,et al.  BMP‐9‐induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/β‐catenin signalling , 2009, Journal of cellular and molecular medicine.

[41]  L. Mirabello,et al.  Osteosarcoma incidence and survival rates from 1973 to 2004 , 2009, Cancer.

[42]  A. Montag,et al.  Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects , 2008, Laboratory Investigation.

[43]  T. He,et al.  Osteosarcoma Development and Stem Cell Differentiation , 2008, Clinical orthopaedics and related research.

[44]  Daniel G. Tenen,et al.  Transcription factors in myeloid development: balancing differentiation with transformation , 2007, Nature Reviews Immunology.

[45]  T. He,et al.  Osteosarcoma and Osteoblastic Differentiation: A New Perspective on Oncogenesis , 2007, Clinical orthopaedics and related research.

[46]  David M. Thomas,et al.  Epigenetic modifications in osteogenic differentiation and transformation , 2006, Journal of cellular biochemistry.

[47]  Lisa L. Wang.  Biology of osteogenic sarcoma. , 2005, Cancer journal.

[48]  Di Chen,et al.  Signal transduction and biological functions of bone morphogenetic proteins. , 2004, Frontiers in bioscience : a journal and virtual library.

[49]  P. Meltzer,et al.  Mechanisms of sarcoma development , 2003, Nature Reviews Cancer.

[50]  F. Dilworth,et al.  Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription , 2001, Oncogene.

[51]  A. Skoultchi,et al.  Reprogramming leukemic cells to terminal differentiation by inhibiting specific cyclin-dependent kinases in G1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[52]  A. Zantema,et al.  Inhibition of cyclin-dependent kinase activity triggers neuronal differentiation of mouse neuroblastoma cells , 1995, The Journal of cell biology.