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Signaling pathways involved in the regulation of osteoblastic cells

Our main research interest is the investigation of signaling pathways involved in the regulation of osteoblastic cells. The cellular and molecular mechanisms responsible for the stimulation of these cells remains uncompletely understood. The comprehension of these mechanisms is of importance for the development of new molecules in the treatment of osteoporosis. In the field of cell signaling, we focused our attention to the role of MAP kinases which are pathways involved in controlling cell proliferation and differentiation. The role of MAP kinases in regulating osteoblastic cells has been investigated in both the non tumoral MC3T3-E1 and primary cultured derived osteoblastic cells. Until recently, we found that the three major MAP kinases are stimulated by serum growth factors. The use of specific MAP kinases inhibitors allowed us to document that these signaling pathways play an important role in the regulation of either the proliferation and/or the differenciation of osteoblastic cells. For instance, we found that the activation of p38 is required for expression of alkaline phosphatase, a key enzyme for the mineralisation of the bone matrix. Recently, we observed that the JNK and to a lesser extent ERK pathways are involved in osteoblastic cell proliferation induced by serum growth factors. Following these observations with serum growth factors, we also found that osteotropic factors such as BMP2, TGF¿, prostaglandins F2¿ and E2 also activate MAP kinases pathways in osteoblastic cells. Recently, we investigated the molecular mechanism by which BMP-2 induces the activation of JNK and p38 in osteoblastic cells and found that protein kinase D (PKD) is involved in this process. Following this observation, we documented that PKD is also involved in activation of JNK and p38 induced by PGF2¿ and PGE2 suggesting an important role of this protein kinase in regulating activation of osteoblastic cells by osteotropic factors. Very recently, genetic studies in human and mouse revealed that the Wnt/LRP5 pathway is an important regulator of the proliferation and of the activity of osteoblastic cells. The molecular mechanisms by which Wnts activate osteoblastic cells is not known and we are presently investigating the effect of Wnts on MAP kinases and activation of osteoblastic cells.

Group's publications

Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms.
BONE
2008 vol. 42(6) pp. 1131-1136
CAVERZASIO J

Prevention of trabecular bone loss induced by estrogen deficiency by a selective p38alpha inhibitor.
JOURNAL OF BONE AND MINERAL RESEARCH
2008 vol. 23(9) pp. 1389-1397
CAVERZASIO J, HIGGINS L, AMMANN P

Evidences for a role of p38 MAP kinase in the stimulation of alkaline phosphatase and matrix mineralization induced by parathyroid hormone in osteoblastic cells
BONE
2007 vol. 41 pp. 59-67
REY A, MANEN D, RIZZOLI R, FERRARI SL, CAVERZASIO J

Essential role of wnt3a-mediated activation of mitogen-activated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralization in C3H10T1/2 mesenchymal cells
ENDOCRINOLOGY
2007 vol. 148 pp. 5323-5330
CAVERZASIO J, MANEN D

Proline-rich motifs in the parathyroid hormone (PTH)/PTH-related protein receptor C terminus mediate scaffolding of c-Src with beta-arrestin2 for ERK1/2 activation
JOURNAL OF BIOLOGICAL CHEMISTRY
2006 vol. 281 pp. 38181-38188
REY A, MANEN D, RIZZOLI R, CAVERZASIO J, FERRARI SL

Enhanced expression of the inorganic phosphate transporter Pit-1 is involved in BMP-2-Induced matrix mineralization in osteoblast-like cells
JOURNAL OF BONE AND MINERAL RESEARCH
2006 vol. 21 pp. 674-683
SUZUKI A, GHAYOR C, GUICHEUX J, MAGNE D, QUILLARD S, KAKITA A, ONO Y, MIURA Y, OISO Y, ITOH M, 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.
JOURNAL OF BIOLOGICAL CHEMISTRY
2004 vol. 279 pp. 259-264
LEMONNIER J, GHAYOR C, GUICHEUX J, 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
JOURNAL OF BONE AND MINERAL RESEARCH
2003 vol. 18 pp. 2060-2068
GUICHEUX J, LEMONNIER J, GHAYOR C, SUZUKI A, PALMER G, CAVERZASIO J

Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation
BONE
2002 vol. 30 pp. 91-98
SUZUKI A, GUICHEUX J, PALMER G, MIURA Y, OISO Y, BONJOUR JP, CAVERZASIO J

Evidence for the involvement of two pathways in activation of extracellular signal-regulated kinase (Erk) and cell proliferation by Gi and Gq protein-coupled receptors in osteoblast-like cells.
JOURNAL OF BONE AND MINERAL RESEARCH
2000 vol. 15 pp. 1697-1706
CAVERZASIO JOSEPH, PALMER G, SUZUKI A, BONJOUR JP

Regulation of alkaline phosphatase activity by p38 MAP kinase in response to activation of Gi protein-coupled receptors by epinephrine in osteoblast-like cells.
ENDOCRINOLOGY
1999 vol. 140 pp. 3177-3182
SUZUKI ATSUSHI, PALMER-LOURENCO GABY, BONJOUR JEAN-PHILIPPE, CAVERZASIO JOSEPH

Research's domains




DATABASE-RESEARCH	GROUP OF CLINICAL BIOLOGY RESEARCH

Joseph CAVERZASIO	Head of group CV	Research subject	Members of the group


	Links about the group Prof. Joseph CAVERZASIO HUG/Spécialités de Médecine Fondation Recherches Médicales 64, avenue de la Roseraie 1205 Genève Suisse Joseph.Caverzasio@unige.ch Tel.: 022/372.99.64 Fax: 022/382.99.73 Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains Signaling pathways involved in the regulation of osteoblastic cells Our main research interest is the investigation of signaling pathways involved in the regulation of osteoblastic cells. The cellular and molecular mechanisms responsible for the stimulation of these cells remains uncompletely understood. The comprehension of these mechanisms is of importance for the development of new molecules in the treatment of osteoporosis. In the field of cell signaling, we focused our attention to the role of MAP kinases which are pathways involved in controlling cell proliferation and differentiation. The role of MAP kinases in regulating osteoblastic cells has been investigated in both the non tumoral MC3T3-E1 and primary cultured derived osteoblastic cells. Until recently, we found that the three major MAP kinases are stimulated by serum growth factors. The use of specific MAP kinases inhibitors allowed us to document that these signaling pathways play an important role in the regulation of either the proliferation and/or the differenciation of osteoblastic cells. For instance, we found that the activation of p38 is required for expression of alkaline phosphatase, a key enzyme for the mineralisation of the bone matrix. Recently, we observed that the JNK and to a lesser extent ERK pathways are involved in osteoblastic cell proliferation induced by serum growth factors. Following these observations with serum growth factors, we also found that osteotropic factors such as BMP2, TGF¿, prostaglandins F2¿ and E2 also activate MAP kinases pathways in osteoblastic cells. Recently, we investigated the molecular mechanism by which BMP-2 induces the activation of JNK and p38 in osteoblastic cells and found that protein kinase D (PKD) is involved in this process. Following this observation, we documented that PKD is also involved in activation of JNK and p38 induced by PGF2¿ and PGE2 suggesting an important role of this protein kinase in regulating activation of osteoblastic cells by osteotropic factors. Very recently, genetic studies in human and mouse revealed that the Wnt/LRP5 pathway is an important regulator of the proliferation and of the activity of osteoblastic cells. The molecular mechanisms by which Wnts activate osteoblastic cells is not known and we are presently investigating the effect of Wnts on MAP kinases and activation of osteoblastic cells. Group's publications Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. BONE 2008 vol. 42(6) pp. 1131-1136 CAVERZASIO J Prevention of trabecular bone loss induced by estrogen deficiency by a selective p38alpha inhibitor. JOURNAL OF BONE AND MINERAL RESEARCH 2008 vol. 23(9) pp. 1389-1397 CAVERZASIO J, HIGGINS L, AMMANN P Evidences for a role of p38 MAP kinase in the stimulation of alkaline phosphatase and matrix mineralization induced by parathyroid hormone in osteoblastic cells BONE 2007 vol. 41 pp. 59-67 REY A, MANEN D, RIZZOLI R, FERRARI SL, CAVERZASIO J Essential role of wnt3a-mediated activation of mitogen-activated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralization in C3H10T1/2 mesenchymal cells ENDOCRINOLOGY 2007 vol. 148 pp. 5323-5330 CAVERZASIO J, MANEN D Proline-rich motifs in the parathyroid hormone (PTH)/PTH-related protein receptor C terminus mediate scaffolding of c-Src with beta-arrestin2 for ERK1/2 activation JOURNAL OF BIOLOGICAL CHEMISTRY 2006 vol. 281 pp. 38181-38188 REY A, MANEN D, RIZZOLI R, CAVERZASIO J, FERRARI SL Enhanced expression of the inorganic phosphate transporter Pit-1 is involved in BMP-2-Induced matrix mineralization in osteoblast-like cells JOURNAL OF BONE AND MINERAL RESEARCH 2006 vol. 21 pp. 674-683 SUZUKI A, GHAYOR C, GUICHEUX J, MAGNE D, QUILLARD S, KAKITA A, ONO Y, MIURA Y, OISO Y, ITOH M, 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. JOURNAL OF BIOLOGICAL CHEMISTRY 2004 vol. 279 pp. 259-264 LEMONNIER J, GHAYOR C, GUICHEUX J, 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 JOURNAL OF BONE AND MINERAL RESEARCH 2003 vol. 18 pp. 2060-2068 GUICHEUX J, LEMONNIER J, GHAYOR C, SUZUKI A, PALMER G, CAVERZASIO J Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation BONE 2002 vol. 30 pp. 91-98 SUZUKI A, GUICHEUX J, PALMER G, MIURA Y, OISO Y, BONJOUR JP, CAVERZASIO J Evidence for the involvement of two pathways in activation of extracellular signal-regulated kinase (Erk) and cell proliferation by Gi and Gq protein-coupled receptors in osteoblast-like cells. JOURNAL OF BONE AND MINERAL RESEARCH 2000 vol. 15 pp. 1697-1706 CAVERZASIO JOSEPH, PALMER G, SUZUKI A, BONJOUR JP Regulation of alkaline phosphatase activity by p38 MAP kinase in response to activation of Gi protein-coupled receptors by epinephrine in osteoblast-like cells. ENDOCRINOLOGY 1999 vol. 140 pp. 3177-3182 SUZUKI ATSUSHI, PALMER-LOURENCO GABY, BONJOUR JEAN-PHILIPPE, CAVERZASIO JOSEPH Research's domains