Mechanotransduction in Bone via Oscillating Fluid Flow

Principal Investigator: Christopher R. Jacobs, PhD

Project Staff: Henry J. Donahue, PhD and R. Lane Smith, PhD

Project Category: Bone & Joint and Osteoporosis - 2004

Objective: Bone cells occupy fluid filled voids (lacunae) in the mineralized matrix and interconnected by small tubes (canaliculi). As the bone matrix is cyclically loaded, fluid flows in the lacunar-canalicular network from regions of high matrix strain to low matrix strain and back in an oscillatory fashion. Although, it has been demonstrated that bone cells respond to steady and pulsatile fluid flow with a transient elevation in intracellular calcium concentration, increased release of paracrine factors, and increased gene transcription, our preliminary data indicate that these responses are fundamentally different from those observed for oscillating flow.

Our central hypothesis is that oscillatory fluid flow in vivo provides an important mechanism of mechanotransduction, and furthermore shear stress level, frequency, time course, low-level steady flow, and cell morphology modulate the cellular response.

Research Plan: This project is divided into four specific aims:

1. Determine the range of frequencies and shear stress magnitudes that are stimulatory to bone cells.

2. The [Ca²⁺]_i, PGE₂, and osteopontin mRNA responses to physiologic oscillating fluid flow applied various times after an initial exposure will be quantified.

3. The [Ca²⁺]_i, PGE₂, and osteopontin mRNA responses to physiologic oscillating fluid flow in combination with low level steady flow will be determined in hFOB cells. We predict that, although insufficient to elicit a response by itself, low-level steady flow will work synergistically with oscillating flow to increase responsiveness to oscillating flow and regulate bone cell metabolism.

4. The geometric dimensions of individual cells will be correlated with [Ca²⁺]_i responsiveness to oscillating fluid flow.

Work Accomplished: All of the work in the project has been completed. Five publications in peer-reviewed journals resulted from the project. A competing renewal application has been completed and is in review at the NIH.

Expected Outcome: The long-term goal of these studies is to better understand the how mechanical loading influences the behavior of bone. Increased understanding of this relationship will lead to the identification of novel targets of therapeutic interventions in bone diseases with a mechanical component such as osteoporosis.

Funding Source: NIH

Funding Status: Active