Mechanical loading by fluid shear stress enhances IGF-1 receptor signaling in osteoblasts in a PKCzeta-dependent manner.
Maintenance of optimal bone physiology requires the coordinated activity of osteoclasts that resorb old bone and osteoblasts that deposit new bone. Mechanical loading of bone and the resulting movement of interstitial fluid within the spaces surrounding bone cells is thought to play a key role is maintaining optimal bone mass. One way in which fluid movement may promote bone formation is by enhancing osteoblast survival. We have shown previously that application of fluid flow to osteoblasts in vitro confers a protective effect by inhibiting osteoblast apoptosis (Pavalko et al., 2003, J. Cell Physiol., 194: 194-205). To investigate the cellular mechanisms that regulate the response of osteoblasts to fluid shear stress, we have examined the possible interaction between fluid flow and growth factors in MC3T3-E1 osteoblast-like cells. We found that insulin-like growth factor-I (IGF-I) was significantly more effective at preventing TNF-alpha-induced apoptosis when cells were first subjected to mechanical loading by exposure to either unidirectional or oscillatory fluid flow compared to cells that were maintained in static culture. Additionally, downstream signaling in response to treatment with IGF-I, including ERK and Akt activation, was enhanced in cells that were subjected to fluid flow, compared to cells maintained in static culture. Furthermore, we found that PKC activity is essential for fluid shear stress sensitization of IGF-IR, since a specific inhibitor of PCKzeta function blocked the flow-enhanced IGF-I-activated Akt and ERK phosphorylation. Together, our results suggest that fluid shear stress may regulate IGF-I signaling in osteoblasts in a PKC-zeta-dependent manner.
Triplett
Jason W
JW
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Medical Science Building, Room 346, Indianapolis, IN 46202-5120, USA.
O'Riley
Rita
R
Tekulve
Kristyn
K
Norvell
Suzanne M
SM
Pavalko
Fredrick M
FM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012212:Rheology / Q000379:methods*; D044967:Serum; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016474:Weight-Bearing; D000099221:Protein Kinase C zeta
D015415:Biomarkers; D003513:Cycloheximide; D048049:Extracellular Signal-Regulated MAP Kinases; D007334:Insulin-Like Growth Factor I; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta