The long-term objective of the proposed studies is to elucidate the mechanism of mechanotransduction inbone. Our present bioengineering-oriented project developed a high-resolution piezoelectric mechanicalloader and evaluated the role of mechanical stimulation in bone using cultured osteoblasts. The resultsreveal that (a) deformation of 3D collagen matrix can induce strain-induced fluid flow; (b) strain-induced fluidflow, and not strain itself, predominantly activates the stress-responsive genes in osteoblasts; and (c)architecture of 3D collagen matrix establishes a pattern of strain-induced fluid flow and molecular transport.Many lines of evidence in animal studies support enhancement of bone remodeling with strain of 1000 -2000 microstrains. An unclear linkage between our in vitro studies and these animal studies is the role ofstrain and fluid flow in bone remodeling. In vitro osteoblast cultures including our current studies use 2Dsubstrates or 3D matrices that hardly mimic the strain-induced fluid flow in vivo. This difference between invitro and in vivo data makes it difficult to evaluate the role of strain and fluid flow in bone remodeling andanti-inflammation. First, microscopic strain in bone might be higher than the macroscopic strain measuredwith strain gauges. A local microscopic strain higher than 1000 - 2000 microstrains may therefore drive fluidflow in bone. Second, the lacunocanalicular network in bone could amplify strain-induced fluid flow in aloading-frequency dependent fashion. Lastly, interstitial fluid flow in bone might be induced by in situ strainas well as strain in a distant location, such that deformation of relatively soft epiphyses induces fluid flow incortical bone in diaphyses.This renewal proposal will use mouse ulnae ex vivo as well as mouse in vivo loading to examine the abovepossible explanations for the data divergence.
Specific aims i nclude: (1) fabricating a piezoelectricmechanical loader for ex vivo and in vivo use; (2) quantifying ex vivo macroscopic and microscopic strainsusing electronic speckle pattern interferometry as well as molecular transport using fluorescence recoveryafter photobleaching; (3) conducting bone histomorphometry to evaluate ex vivo data; and (4) examiningload-driven adverse effects with gene expression and enzyme activities (e.g., matrix metalloproteinases).Mechanical loads will be given in the ulna-loading (axial loading) and elbow-loading (lateral loading) modes.These two modes have been shown to enhance bone remodeling in the diaphysis with different patterns ofstrain distribution. Successful completion of the proposed renewal proposal will provide basic knowledgeabout induction of fluid flow in bone and establish a research platform for devising therapeutic strategies forstrengthening bone and preventing bone loss.
Showing the most recent 10 out of 45 publications