MULTIPLE EXTRACELLULAR SIGNALS PROMOTE OSTEOBLAST SURVIVAL AND APOPTOSIS

Programed cell death (PCD) or apoptosis is a naturally occurring cell suicide pathway induced in a variety of cell types. In many cases, PCD apparently arises as a result of competition for limiting amounts of survival signals. In this study, we have investigated the potential ro le of growth factors (GF), cytokines, and osteotropic hormones on oste oblast survival in vitro. Our results indicate that in the absence of any of these factors, osteoblasts rapidly undergo PCD, as determined b y cell morphology, mitochondrial function, and nuclei fragmentation. m entation. Osteoblast survival was promoted by insulin-like growth fact or I (IGF-I), IGF-II, insulin, and basic fibroblast growth factor (bFG F). Platelet-derived growth factor had no effect an osteoblast surviva l, but this GF potentiated the survival-promoting effects of IGF-I, IG F-II, and insulin. A similar effect occurred when bFGF was added in co mbination with either of the IGFs or insulin. The effects of the IGFs were blocked by alpha IR-3, an antibody to the type I IGF receptor, wh ereas the effects of insulin were only partially blocked. This antibod y blocked the potentiating effects of platelet-derived growth factor o n IGF-I-mediated osteoblast survival, but only partially blocked those of bFGF. Although a 100% survival of osteoblasts was seen in the pres ence of 2% FCS, the highest level attained by any of the above GF comb inations was similar to 75%. The monocyte-derived factor, tumor necros is factor-alpha (TNF alpha) was the only agent that enhanced PCD in th is study. These results suggest that osteoblast survival is promoted b y those GFs sequestrated in bone matrix and that the type I, but not t he type II, IGF receptor is involved in the response. Our data also in dicate that other unidentified GFs or components of the extracellular matrix may be involved in promoting osteoblast survival and that TNF a lpha may abrogate their effects in vivo. We propose that these GFs may be released from bone matrix during phases of bone resorption and pro mote osteoblast survival, thereby playing an important role in bone re modeling, and that PCD induced by TNF alpha may contribute to the bone loss in inflammatory bone disease.