TY - JOUR
T1 - LDL induces Saos2 osteoblast death via Akt pathways responsive to a neutral sphingomyelinase inhibitor
AU - Klein, Benjamin Y.
AU - Kerem, Zohar
AU - Rojansky, Nathan
PY - 2006/6/1
Y1 - 2006/6/1
N2 - Atherosclerosis is epidemiologically associated with postmenopausal osteoporosis (OP) presumably by common etiologic factors, reflecting a state of co-morbidity in aging. Osteoblasts make a significant facet of this comorbidity state. Since oxidized low-density I ipoprotein (oxLDL) is a major factor in generation of vascular wall pathology, we examined the ability of native LDL (nLDL) and oxLDL to induce Saos2 osteoblasts growth arrest. OxLDL induced Saos2 cell death with morphological features of apoptosis that was inhibited mainly by caspase-9 and partially by caspase-3 but not by caspase-8 inhibitors. nLDL, like oxLDL, has induced cell death, where 60% (P = 0.00033) and 30% (P = 0.075, ns) of the cell death, respectively, could be inhibited by scyphostatin (a neutral sphingomyelinase [nSMase] inhibitor). Upon similar condition, nLDL inhibited the phosphorylation of Akt and two of its downstream targets, fork head receptor (FKHR) and glycogen synthase kinase-3 (GSK3). This is a pathway that stimulates cell survival and proliferation. nLDL has also induced an increase in the proapoptotic Bcl-Xs and it has diminished the potential antiapoptotic Src kinase activity. At the 4 h time-point, upon a substantial decrease in nLDL-induced Akt phosphorylation, scyphostatin has inhibited the reduction in FKHR and GSK3 phosphorylation but inexplicably not that of Akt. Scyphostatin has also corrected the reduction in Src kinase activity. Taken together, the results indicate that nLDL has induced apoptosis in Saos2 osteoblasts by inactivation of the pathway downstream to Akt using nSMase, and by involvement of Src kinase. Inferring that caspase-9 was the main executioner (rather than caspase-8 and-3) in Saos2 cell death, indicates that the nSMase-induced release of ceramide, directly activated the intrinsic mitochondrial apoptotic pathway. With regard to the Akt inactivation by nLDL, Saos2 osteoblasts responded in an opposite fash ion to the response reported by others, in macrophages.
AB - Atherosclerosis is epidemiologically associated with postmenopausal osteoporosis (OP) presumably by common etiologic factors, reflecting a state of co-morbidity in aging. Osteoblasts make a significant facet of this comorbidity state. Since oxidized low-density I ipoprotein (oxLDL) is a major factor in generation of vascular wall pathology, we examined the ability of native LDL (nLDL) and oxLDL to induce Saos2 osteoblasts growth arrest. OxLDL induced Saos2 cell death with morphological features of apoptosis that was inhibited mainly by caspase-9 and partially by caspase-3 but not by caspase-8 inhibitors. nLDL, like oxLDL, has induced cell death, where 60% (P = 0.00033) and 30% (P = 0.075, ns) of the cell death, respectively, could be inhibited by scyphostatin (a neutral sphingomyelinase [nSMase] inhibitor). Upon similar condition, nLDL inhibited the phosphorylation of Akt and two of its downstream targets, fork head receptor (FKHR) and glycogen synthase kinase-3 (GSK3). This is a pathway that stimulates cell survival and proliferation. nLDL has also induced an increase in the proapoptotic Bcl-Xs and it has diminished the potential antiapoptotic Src kinase activity. At the 4 h time-point, upon a substantial decrease in nLDL-induced Akt phosphorylation, scyphostatin has inhibited the reduction in FKHR and GSK3 phosphorylation but inexplicably not that of Akt. Scyphostatin has also corrected the reduction in Src kinase activity. Taken together, the results indicate that nLDL has induced apoptosis in Saos2 osteoblasts by inactivation of the pathway downstream to Akt using nSMase, and by involvement of Src kinase. Inferring that caspase-9 was the main executioner (rather than caspase-8 and-3) in Saos2 cell death, indicates that the nSMase-induced release of ceramide, directly activated the intrinsic mitochondrial apoptotic pathway. With regard to the Akt inactivation by nLDL, Saos2 osteoblasts responded in an opposite fash ion to the response reported by others, in macrophages.
KW - Akt/PKB
KW - Atherosclerosis
KW - Co-morbidity
KW - LDL
KW - Osteoporosis
KW - Sphyngomyelinase
KW - Src-kinase
UR - http://www.scopus.com/inward/record.url?scp=33646567843&partnerID=8YFLogxK
U2 - 10.1002/jcb.20807
DO - 10.1002/jcb.20807
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 16440306
AN - SCOPUS:33646567843
SN - 0730-2312
VL - 98
SP - 661
EP - 671
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
IS - 3
ER -