A model for the role of integrins in flow induced mechanotransduction in osteocytes.
A fundamental paradox in bone mechanobiology is that tissue-level strains caused by human locomotion are too small to initiate intracellular signaling in osteocytes. A cellular-level strain-amplification model previously has been proposed to explain this paradox. However, the molecular mechanism for initiating signaling has eluded detection because none of the molecules in this previously proposed model are known mediators of intracellular signaling. In this paper, we explore a paradigm and quantitative model for the initiation of intracellular signaling, namely that the processes are attached directly at discrete locations along the canalicular wall by beta(3) integrins at the apex of infrequent, previously unrecognized canalicular projections. Unique rapid fixation techniques have identified these projections and have shown them to be consistent with other studies suggesting that the adhesion molecules are alpha(v)beta(3) integrins. Our theoretical model predicts that the tensile forces acting on the integrins are <15 pN and thus provide stable attachment for the range of physiological loadings. The model also predicts that axial strains caused by the sliding of actin microfilaments about the fixed integrin attachments are an order of magnitude larger than the radial strains in the previously proposed strain-amplification theory and two orders of magnitude greater than whole-tissue strains. In vitro experiments indicated that membrane strains of this order are large enough to open stretch-activated cation channels.
Wang
Yilin
Y
Department of Biomedical Engineering, The City College of New York and the Graduate Center, City University of New York, New York, NY 10031, USA.
McNamara
Laoise M
LM
Schaffler
Mitchell B
MB
Weinbaum
Sheldon
S
D000199:Actins / Q000502:physiology; D000818:Animals; D016023:Integrins / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D008954:Models, Biological; D010011:Osteocytes / Q000502:physiology*
D000199:Actins; D016023:Integrins