Transforming Growth Factor-β1 (TGF-β1) Induces Human Osteoclast Apoptosis by Up-regulating Bim

Transforming growth factor-β1 (TGF-β1) is the most abundant TGF-β isoform detected in bone and is an important functional modulator of osteoclasts. TGF-β1 can induce osteoclast apoptosis; however, the apoptotic pathways involved in this process are not known. We show here that human osteoclasts express both type-I and type-II TGF-β receptors. In the absence of survival factors, TGF-β1 (1 ng/ml) induced osteoclast apoptosis. The expression of activated caspase-9, but not that of caspase-8, was increased by TGF-β1 stimulation, and the rate of TGF-β1-induced apoptosis was significantly lower in the presence of a caspase-9 inhibitor. To study further the mechanisms involved in TGF-β1-induced osteoclast apoptosis, we investigated TGF-β1 signaling, which primarily involves the Smad pathway, but also other pathways that may interfere with intracellular modulators of apoptosis, such as mitogen-activated protein (MAP) kinases and Bcl2 family members. We show here that early events consisted of a trend toward increased expression of extracellular signal-regulated kinase (ERK), and then TGF-β1 significantly induced the activation of p38 and Smad2 in a time-dependent manner. These signaling cascades may activate the intrinsic apoptosis pathway, which involves Bim, the expression of which was increased in the presence of TGF-β1. Furthermore, the rate of TGF-β1-induced osteoclast apoptosis was lower when Bim expression was suppressed, and inhibiting the Smad pathway abolished Bim up-regulation following TGF-β stimulation. This could correspond to a regulatory mechanism involved in the inhibition of osteoclast activity by TGF-β1. Transforming growth factor-β1 (TGF-β1) is the most abundant TGF-β isoform detected in bone and is an important functional modulator of osteoclasts. TGF-β1 can induce osteoclast apoptosis; however, the apoptotic pathways involved in this process are not known. We show here that human osteoclasts express both type-I and type-II TGF-β receptors. In the absence of survival factors, TGF-β1 (1 ng/ml) induced osteoclast apoptosis. The expression of activated caspase-9, but not that of caspase-8, was increased by TGF-β1 stimulation, and the rate of TGF-β1-induced apoptosis was significantly lower in the presence of a caspase-9 inhibitor. To study further the mechanisms involved in TGF-β1-induced osteoclast apoptosis, we investigated TGF-β1 signaling, which primarily involves the Smad pathway, but also other pathways that may interfere with intracellular modulators of apoptosis, such as mitogen-activated protein (MAP) kinases and Bcl2 family members. We show here that early events consisted of a trend toward increased expression of extracellular signal-regulated kinase (ERK), and then TGF-β1 significantly induced the activation of p38 and Smad2 in a time-dependent manner. These signaling cascades may activate the intrinsic apoptosis pathway, which involves Bim, the expression of which was increased in the presence of TGF-β1. Furthermore, the rate of TGF-β1-induced osteoclast apoptosis was lower when Bim expression was suppressed, and inhibiting the Smad pathway abolished Bim up-regulation following TGF-β stimulation. This could correspond to a regulatory mechanism involved in the inhibition of osteoclast activity by TGF-β1. Bone remodeling is a highly controlled physiological process that results from the balance between the formation and resorption of bone. Disruption of this equilibrium can give rise to bone disorders characterized by excessive bone resorption, such as osteoporosis (1.Riggs B.L. Parfitt A.M. J. Bone. Miner. Res. 2005; 20: 177-184Crossref PubMed Scopus (292) Google Scholar). The bone resorbing cells, known as osteoclasts, are large, multinucleated cells (MNCs) 2The abbreviations used are: MNCmultinucleated cellTGF-β1transforming growth factor-β1TGF-β-Rtransforming growth factor-β receptorTRAILTNF-related apoptosis-inducing ligandRANKreceptor activator of NF-κBRANKLreceptor activator of NF-κB ligandMAPmitogen-activated proteinMAPKMAP kinaseERKextracellular signal-regulated kinaseJNKc-Jun NH2-terminal kinaseM-CSFmacrophage-colony-stimulating factorCBMcord blood monocyteZbenzyloxycarbonylsiRNAsmall interfering RNA.2The abbreviations used are: MNCmultinucleated cellTGF-β1transforming growth factor-β1TGF-β-Rtransforming growth factor-β receptorTRAILTNF-related apoptosis-inducing ligandRANKreceptor activator of NF-κBRANKLreceptor activator of NF-κB ligandMAPmitogen-activated proteinMAPKMAP kinaseERKextracellular signal-regulated kinaseJNKc-Jun NH2-terminal kinaseM-CSFmacrophage-colony-stimulating factorCBMcord blood monocyteZbenzyloxycarbonylsiRNAsmall interfering RNA. of hematopoietic origin. Under the control of local and systemic factors, mainly macrophage-colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL), monocyte/macrophage precursor cells undergo osteoclast differentiation, and this eventually leads to the formation of active bone-resorbing cells (2.Boyle W.J. Simonet W.S. Lacey D.L. Nature. 2003; 423: 337-342Crossref PubMed Scopus (4727) Google Scholar). multinucleated cell transforming growth factor-β1 transforming growth factor-β receptor TNF-related apoptosis-inducing ligand receptor activator of NF-κB receptor activator of NF-κB ligand mitogen-activated protein MAP kinase extracellular signal-regulated kinase c-Jun NH2-terminal kinase macrophage-colony-stimulating factor cord blood monocyte benzyloxycarbonyl small interfering RNA. multinucleated cell transforming growth factor-β1 transforming growth factor-β receptor TNF-related apoptosis-inducing ligand receptor activator of NF-κB receptor activator of NF-κB ligand mitogen-activated protein MAP kinase extracellular signal-regulated kinase c-Jun NH2-terminal kinase macrophage-colony-stimulating factor cord blood monocyte benzyloxycarbonyl small interfering RNA. Most of the factors identified as affecting bone resorption enhance osteoclast formation or activity, but few factors have been shown to inhibit these processes. One important way to reduce osteoclast-resorbing activity is to induce osteoclast apoptosis (3.Roux S. Chamoux E. Pickens C.O. Cell Apoptotic Signaling Pathways. Nova Science Publishers, Hauppauge, NY2007: 163-184Google Scholar). In recent years, there has been growing evidence to suggest that osteoclast apoptosis could be modulated by locally released signals. For instance, we and others have demonstrated the role of the TNF-related apoptosis-inducing ligand (TRAIL) pathway in osteoclast regulation (4.Brunetti G. Oranger A. Mori G. Tamma R. Di Benedetto A. Pignataro P. Grassi F.R. Zallone A. Grano M. Colucci S. Ann. N.Y. Acad. Sci. 2007; 1116: 316-322Crossref PubMed Scopus (10) Google Scholar, 5.Colucci S. Brunetti G. Cantatore F.P. Oranger A. Mori G. Pignataro P. Tamma R. Grassi F.R. Zallone A. Grano M. Apoptosis. 2007; 12: 1623-1632Crossref PubMed Scopus (47) Google Scholar, 6.Roux S. Lambert-Comeau P. Saint-Pierre C. Lépine M. Sawan B. Parent J.L. Biochem. Biophys. Res. Commun. 2005; 333: 42-50Crossref PubMed Scopus (62) Google Scholar). We have also shown that TRAIL is expressed by osteoclasts deprived of survival factors and that this is part of an autocrine loop that modulates osteoclast survival and thus bone remodeling (7.Chamoux E. Houde N. L'Eriger K. Roux S. J. Cell. Physiol. 2008; 216: 536-542Crossref PubMed Scopus (56) Google Scholar). Transforming growth factor-β1 (TGF-β1) is an important functional modulator of osteoclasts. TGF-β plays a major role in the proliferation, migration, differentiation, and survival of many cell types (8.Rahimi R.A. Leof E.B. J. Cell. Biochem. 2007; 102: 593-608Crossref PubMed Scopus (318) Google Scholar). The actions of TGF-β require first its binding to the TGF-β type-II receptor (TGF-β-RII) followed by the recruitment of TGF-β-RI. These ligand-receptor interactions lead to the phosphorylation of two cytoplasmic adaptors, Smad2 and Smad3, that in turn recruit Smad4 to form a trimeric complex of intracellular mediators that can enter the nucleus and initiate gene transcription (9.Massagué J. Seoane J. Wotton D. Genes. Dev. 2005; 19: 2783-2810Crossref PubMed Scopus (1881) Google Scholar). TGF-β is also able to activate the MAP kinases ERK, p38, and JNK by alternative pathways (10.Javelaud D. Mauviel A. Oncogene. 2005; 24: 5742-5750Crossref PubMed Scopus (342) Google Scholar). TGF-β is known to influence bone metabolism in various ways. Firstly, TGF-β acts on bone formation by up-regulating the recruitment and proliferation of osteoblast precursors and by inhibiting their apoptosis (11.Janssens K. ten Dijke P. Janssens S. Van Hul W. Endocr. Rev. 2005; 26: 743-774Crossref PubMed Scopus (549) Google Scholar). Secondly, TGF-β indirectly slows the formation and activation of osteoclasts by reducing RANKL expression and increasing osteoprotegerin production by osteoblasts (12.Takai H. Kanematsu M. Yano K. Tsuda E. Higashio K. Ikeda K. Watanabe K. Yamada Y. J. Biol. Chem. 1998; 273: 27091-27096Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). On the other hand, TGF-β has direct and contradictory actions on osteoclasts by limiting both the proliferation and the fusion of osteoclast precursors and enhancing RANKL-mediated differentiation (13.Fuller K. Lean J.M. Bayley K.E. Wani M.R. Chambers T.J. J. Cell. Sci. 2000; 113: 2445-2453Crossref PubMed Google Scholar, 14.Orcel P. Bielakoff J. De Vernejoul M.C. J. Cell. Physiol. 1990; 142: 293-298Crossref PubMed Scopus (13) Google Scholar). In addition, TGF-β is a potent inducer of osteoclast apoptosis, although the mechanisms involved remain poorly understood (6.Roux S. Lambert-Comeau P. Saint-Pierre C. Lépine M. Sawan B. Parent J.L. Biochem. Biophys. Res. Commun. 2005; 333: 42-50Crossref PubMed Scopus (62) Google Scholar, 15.Hughes D.E. Dai A. Tiffee J.C. Li H.H. Mundy G.R. Boyce B.F. Nat. Med. 1996; 2: 1132-1136Crossref PubMed Scopus (684) Google Scholar). Our aim was to investigate the mechanisms of TGF-β-induced osteoclast apoptosis in human osteoclasts differentiated from cord blood monocytes (CBMs). We show here that TGF-β1 activates the intrinsic pathway of apoptosis in osteoclasts. We also show that the p38 and Smad pathways may be involved in mediating the actions of TGF-β and that Bim expression could be necessary for the execution of apoptosis. Recombinant human M-CSF, recombinant human GM-CSF, and caspase inhibitors were purchased from R&D systems (Minneapolis, MN); recombinant human TGF-β1 was obtained from Peprotech (Rocky Hill, NJ); staurosporine, monoclonal mouse antibodies directed against caspase-8, cleaved caspase-8, rabbit polyclonal antibodies against caspase-9, cleaved caspase-9, all anti-MAP kinases and anti-Smad antibodies, as well as the rabbit polyclonal antibody against actin came from Cell Signaling Technologies (Danvers, MA). The rabbit polyclonal antibody against TGF-β type-I and type-II receptors and the rabbit polyclonal antibody against Bcl-2 homologous were both purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Normal goat, rabbit, and mouse serum and LSAB2 staining kit were obtained from DAKO (Glostrup, Denmark). Soluble human RANKL was produced in our laboratory. Umbilical cord blood from normal pregnant women was obtained at delivery after informed consent. Mononuclear leukocyte suspensions were isolated from the cord blood by density-gradient centrifugation and then washed and suspended in OPTI-MEM (Invitrogen, Burlington, Ontario, Canada) with antibiotics (1 IU/ml penicillin, 100 mg/ml streptomycin, 0.5 mg/ml amphotericin B) and 2% fetal bovine serum (Wisent, Montréal, PQ). They were plated at a density of 3 × 106 cells/ml. After incubating overnight, the cells were washed to remove non-adherent cells. The selected CBMs were cultured for another 3 weeks, in the same medium supplemented with GM-CSF (100 pg/ml), for the first 3 days and then with M-CSF (25 ng/ml) and RANKL (100 ng/ml). The medium was changed twice weekly. We have previously shown that fully differentiated osteoclasts form under these conditions (6.Roux S. Lambert-Comeau P. Saint-Pierre C. Lépine M. Sawan B. Parent J.L. Biochem. Biophys. Res. Commun. 2005; 333: 42-50Crossref PubMed Scopus (62) Google Scholar, 16.Roux S. Quinn J. Pichaud F. Orcel P. Chastre E. Jullienne A. De Vernejoul M.C. J. Cell. Physiol. 1996; 168: 489-498Crossref PubMed Google Scholar). After 3 weeks of culture in eight-chamber Labtecks, mature cells were fixed with 1% paraformaldehyde in phosphate-buffered saline. Nonspecific binding sites were blocked with 5% skimmed milk, and the cells were then incubated overnight at 4 °C with the antibody directed against human cleaved or cleaved caspase-9 or with the same of normal or mouse After the were to in phosphate-buffered for to were then with antibody and from the LSAB2 was with which rise to a been To multinucleated cells, the were with To osteoclast were after M-CSF and as well as reducing fetal bovine serum to 1% in the OPTI-MEM for to the TGF-β1 (1 ng/ml) or (1 was then for various of The cells were then washed twice for on in 1% of were by and to a MA). The was blocked with 5% skimmed and incubated overnight at 4 °C with the For these we used antibodies against caspase-9 JNK and and p38 and Smad2 and and and Bim antibodies were used as a The were then washed incubated for at with a or antibodies were by an were by and for the density of the actin after and the apoptosis was after M-CSF and as well as reducing fetal bovine serum to 1% in the OPTI-MEM for to the The kit was then used to and apoptosis. This in of at the cell The cells were and in an for at They were then washed with phosphate-buffered for were by for at was then followed by the The an The were then with for at to multinucleated cells with or nuclear The were a and the multinucleated cells were the differentiated cells were with Bim or Smad2 Ontario, Canada) in a in were incubated at °C for The was by in well of the culture a control protein and the of Bim or Smad2 was by stimulation, the medium was and with and OPTI-MEM 1% fetal bovine are expressed as and the was by a or of with was as was used to and on the cell of osteoclasts polyclonal antibodies against and and was on which with the on The of cells that of expressed expressed These show that both the and the receptors were expressed at the of human osteoclasts, that TGF-β could be to these receptors and a direct as a the of the after the M-CSF and RANKL been of TGF-β1 were the apoptosis was ng/ml). that the of apoptotic was in the absence of TGF-β1 and significantly increased in the presence of TGF-β1 at a of and In in the presence of the of apoptotic were lower and TGF-β1 induced osteoclast apoptosis, although in cells. To which apoptosis pathway was activated in to TGF-β1 stimulation, we the of of and caspase-9, of the activation of the and intrinsic apoptotic In of cleaved was after TGF-β1 stimulation. In increased of caspase-9 after to TGF-β1. (1 was used as a control of apoptosis and of the activation of and caspase-9 results the which cells other osteoclasts, TGF-β-induced caspase activation in osteoclast was also by antibodies against the cleaved of activated and caspase-9 expression was the same in cells and in cells that been with TGF-β1 (1 ng/ml) for was significantly increased in the presence of In the of with caspase-9 antibodies was significantly increased by TGF-β1 when with cells These suggest that TGF-β1 induced apoptosis by caspase-9, and the intrinsic pathway, in human osteoclasts. To further the of the intrinsic pathway in the TGF-β-induced apoptosis, apoptosis were in the presence of caspase were deprived of survival factors and for and then with caspase inhibitors for to TGF-β1 for was detected in of the this to the of apoptosis after survival factor apoptosis was significantly increased in that been to TGF-β1 for a with a caspase-9 TGF-β1-induced apoptosis, and the was to that of cells. In the of a not apoptosis in cells. These results that the activation of caspase-9, but not that of caspase-8, is involved in TGF-β1-induced apoptosis in human osteoclasts. To further the activation of caspase-9 by we investigated the signaling cascades activated in to stimulation. The known signaling cascades activated by Smad and and were investigated by TGF-β1 induced and phosphorylation of after which at and then TGF-β1 induced activation of p38 after with a in phosphorylation when with cells activation of Smad2 was detected from its phosphorylation after TGF-β1 which activation of the Smad pathway we not of JNK phosphorylation 3 after TGF-β1 stimulation, that this may not be involved in TGF-β in osteoclasts under these conditions The complex of Smad after TGF-β acts a transcription the increased activity of ERK, p38, and Smad2 may gene we the expression of Bcl-2 by after of TGF-β1 We not in the expression of the protein Bcl-2 or in the expression of the although this was not we a trend toward increased expression of the protein after when with Furthermore, a and of Bim expression was detected after of TGF-β1 when with This that increased expression of the protein Bim could be involved in TGF-β1-induced apoptosis in human osteoclasts. To further investigate Bim expression was to TGF-β1-induced apoptosis, we Bim expression by were then to and then caspase-9 and apoptosis were that caspase-9 to the same in cells and in cells that were with the control in the This a of the process in caspase-9 activation in our TGF-β1 stimulation, of the were with caspase-9 antibodies after a significantly was in cells this TGF-β-induced of caspase-9 was abolished when cells were with Bim TGF-β1-induced apoptosis was in cells that or not been with Bim In cells, apoptosis was significantly increased from in cells to in that been to TGF-β1 (1 ng/ml) for Bim TGF-β1-induced apoptosis and To further the Smad pathway was to the in Bim we Smad2 expression by of Bim was by in cells by Smad2 The in Bim expression after to TGF-β1 (1 ng/ml) for was in cells cultured in the presence of Smad2 and TGF-β has previously been as apoptosis in and human osteoclasts (6.Roux S. Lambert-Comeau P. Saint-Pierre C. Lépine M. Sawan B. Parent J.L. Biochem. Biophys. Res. Commun. 2005; 333: 42-50Crossref PubMed Scopus (62) Google Scholar, 15.Hughes D.E. Dai A. Tiffee J.C. Li H.H. Mundy G.R. Boyce B.F. Nat. Med. 1996; 2: 1132-1136Crossref PubMed Scopus (684) Google and in the we investigated the of events to such We have shown that TGF-β receptors and were expressed at the of human osteoclasts and that TGF-β1 induced osteoclast apoptosis by the intrinsic pathway of apoptosis to caspase-9 Furthermore, we have demonstrated that TGF-β1 induced a trend toward an early in ERK, the phosphorylation of p38 and and Bim which was to the TGF-β1-induced osteoclast apoptosis. TGF-β has a complex role in bone cells and bone In human bone TGF-β1 is known to be a potent of osteoclast formation C. J. Mundy G.R. Acad. Sci. PubMed Scopus (251) Google Scholar). TGF-β RANKL expression and osteoprotegerin expression by osteoblasts in thus indirectly osteoclast differentiation and by the (12.Takai H. Kanematsu M. Yano K. Tsuda E. Higashio K. Ikeda K. Watanabe K. Yamada Y. J. Biol. Chem. 1998; 273: 27091-27096Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). TGF-β may also have a direct on osteoclasts. TGF-β could osteoclast formation by and expression when at an early of the osteoclast differentiation (13.Fuller K. Lean J.M. Bayley K.E. Wani M.R. Chambers T.J. J. Cell. Sci. 2000; 113: 2445-2453Crossref PubMed Google Scholar, 14.Orcel P. Bielakoff J. De Vernejoul M.C. J. Cell. Physiol. 1990; 142: 293-298Crossref PubMed Scopus (13) Google Scholar, K.E. Biochem. Biophys. Res. Commun. 2008; PubMed Scopus Google Scholar). TGF-β is known to induce apoptosis in mature osteoclasts (6.Roux S. Lambert-Comeau P. Saint-Pierre C. Lépine M. Sawan B. Parent J.L. Biochem. Biophys. Res. Commun. 2005; 333: 42-50Crossref PubMed Scopus (62) Google Scholar, 15.Hughes D.E. Dai A. Tiffee J.C. Li H.H. Mundy G.R. Boyce B.F. Nat. Med. 1996; 2: 1132-1136Crossref PubMed Scopus (684) Google Scholar). In have that bone increased when TGF-β pathways were by inhibition of the type-I receptor or by of the protein 3 B. R. Y. G. Bone. 2005; PubMed Scopus Google Scholar, G. E. H. M. R. PubMed Scopus Google the of TGF-β on bone as a of its on bone cells, as well as on other cells. The presence of TGF-β receptors has been detected in osteoclasts from cell of bone that are in a A. S. C. M. PubMed Scopus Google Scholar, Y. M. J.M. J. Google Scholar). We here that in other human osteoclasts express the TGF-β type-I and type-II receptors. The intracellular pathways activated TGF-β-induced apoptosis have been in of cell types S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. S. N. P. R. ten Dijke P. M. Biol. Cell. 2003; PubMed Scopus Google Scholar, M. S. H. K. A. S. Cell. Biol. 2005; PubMed Scopus Google Scholar, S. A. J. Oncogene. 2007; 26: PubMed Scopus Google Scholar, A. Biochem. Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar). The mechanisms used by TGF-β to induce apoptosis on the cell and may protein kinases the MAP kinases p38 and or the Smad pathway S. J. J. J. 2008; PubMed Scopus Google Scholar, J. M. B. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M.C. J. PubMed Scopus Google Scholar). We the activation of p38 and Smad2 TGF-β-induced osteoclast apoptosis the p38 pathway is known to be involved in TGF-β-induced apoptosis, the activation of the p38 pathway has also been and with increased J.M. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, P. K. H. J.M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). This the of between pathways and the of the on systems J.M. Med. Full Text Full Text PDF PubMed Scopus Google Scholar). The phosphorylation of Smad2 leads to the formation of a complex with and Smad4 that is the nucleus the transcription of (11.Janssens K. ten Dijke P. Janssens S. Van Hul W. Endocr. Rev. 2005; 26: 743-774Crossref PubMed Scopus (549) Google Scholar). The transcription of Bcl-2 has been in TGF-β-induced apoptosis S. A. J. Oncogene. 2007; 26: PubMed Scopus Google Scholar). These two pathways p38 and were for TGF-β-induced osteoclast apoptosis as their activation is known to enhance the transcription of various M. S. H. K. A. S. Cell. Biol. 2005; PubMed Scopus Google Scholar, M. G. 2008; PubMed Scopus Google Scholar, S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In bone TGF-β1 has been shown to osteoclast apoptosis in in the presence of RANKL A. M. Cell. Res. 2008; PubMed Scopus Google Scholar). which is an osteoclast survival may activate many signaling pathways that could with TGF-β signaling and the balance between osteoclast or (3.Roux S. Chamoux E. Pickens C.O. Cell Apoptotic Signaling Pathways. Nova Science Publishers, Hauppauge, NY2007: 163-184Google Scholar). To these types of we TGF-β-induced apoptosis in osteoclasts cultured in the presence of RANKL and not of TGF-β1 on osteoclast apoptosis under the same conditions although apoptosis was induced with a of TGF-β1 ng/ml). This could for the between our results and of A. M. Cell. Res. 2008; PubMed Scopus Google Scholar). This may also to the to TGF-β in the of bone TGF-β is a major in the in which bone factors that activate osteoclasts to to an increased TGF-β from the bone which in turn growth and protein protein is a potent of RANKL production by thus the J.M. 2007; PubMed Scopus Google Scholar). Under these TGF-β is with and growth factors that osteoclast formation and Our that TGF-β1-induced apoptosis on the activation of the intrinsic pathway and caspase-9 a of the pathway, is not induced by TGF-β but a of This is to the presence and activity of TRAIL that is produced by osteoclasts when are deprived of survival factors, as previously (7.Chamoux E. Houde N. L'Eriger K. Roux S. J. Cell. Physiol. 2008; 216: 536-542Crossref PubMed Scopus (56) Google Scholar). however, not to that TGF-β1 not activate as its receptors not a receptor intracellular The activation of caspase-9 however, on the expression of Bim, a of the Bcl2 We here that Bim expression is to TGF-β1-induced apoptosis, as has been in other cell types M. S. H. K. A. S. Cell. Biol. 2005; PubMed Scopus Google Scholar, S. A. J. Oncogene. 2007; 26: PubMed Scopus Google Scholar, S. J. J. J. 2008; PubMed Scopus Google Scholar). In addition, Bim to be for the regulation of apoptosis in osteoclasts as this protein is induced in osteoclasts, and osteoclasts from are to the of apoptosis P. Y. H. A. A. H. A. R. H. H. K. A. S. J. 2003; PubMed Scopus Google Scholar). In our although the absence of survival factors could have induced increased Bim we show that in the absence of Bim TGF-β1-induced apoptosis not in osteoclasts. In addition, under the control of signaling, an up-regulation of Bim to be for TGF-β-induced apoptosis in cells J. A. G. Y. J. K. J. Y. J. Cell. Physiol. 2008; PubMed Scopus (47) Google Scholar). In the absence of survival factors such as TGF-β1 induced apoptosis in our of human osteoclast differentiation and also activated both the Smad signaling pathways and the p38 up-regulation of Bim expression was involved in the intrinsic apoptotic pathway, to osteoclast apoptosis. Bim to an important role in the TGF-β-induced osteoclast apoptosis, further are necessary to this to the activation of the Smad pathway in our although this is by previously and our results suggest that this could be by the Smad2 In addition, we that p38 may a role as the p38 pathway the of apoptosis the activation of caspase-9 but not of A. Rev. 2005; PubMed Scopus Google however, the mechanisms involved remain to be This of TGF-β1 on osteoclasts could be with the that TGF-β acts as a in bone After bone resorption has TGF-β is locally released from the bone and then bone resorption by osteoclast apoptosis and by bone with

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