BNG-338: Lecture 11. Outlines due today Exam #1 on Friday Review Molecular Level Mechanobiology Cellular Level Mechanobiology. Monday, May 15, 17

Transcription

1 BNG-338: Lecture 11 Outlines due today Exam #1 on Friday Review Molecular Level Mechanobiology Cellular Level Mechanobiology

2 Learning Objectives Review how cells sense strain on a molecular level Discover how research is done to determine the cells ability to sense strain Explain how cells sense strain on a cellular level Describe the role of fluid shear stress in use, overuse, and disuse of bone Describe the events in bone maintenance during fatigue Describe the primary cilium and its role in mechanosensing

3 Some Mechanobiological Parameters at Different Levels of Consideration Molecular Level Cytoskeletal changes Stretch-activated ion channels Integrins Growth factors Cytokines Receptors Cellular Level Cell Pressure Cell Shape Changes Cell-matrix interactions Oxygen/nutrient supply Electric Potentials Temperature Tissue Level Stress/Strain Hydrostatic Stress/Strain Shear Stress/Strain Strain Energy Density Fatigue Damage Stress/Strain History Organ Level Force Displacement Stiffness Failure Load Loading Rate Loading History

4 Integrins

5 Biochemical Coupling Ion channels~ stretch activated channel was a potassium channel Fluid flow has been shown to induce an influx of extracellular Ca 2+ into the osteoblast

6 Some Mechanobiological Parameters at Different Levels of Consideration Molecular Level Cytoskeletal changes Stretch-activated ion channels Integrins Growth factors Cytokines Receptors Cellular Level Cell Pressure Cell Shape Changes Cell-matrix interactions Oxygen/nutrient supply Electric Potentials Temperature Tissue Level Stress/Strain Hydrostatic Stress/Strain Shear Stress/Strain Strain Energy Density Fatigue Damage Stress/Strain History Organ Level Force Displacement Stiffness Failure Load Loading Rate Loading History

7 Osteocytes: Strain Gages? ~95% of cells in the adult skeleton are osteocytes and bone lining cells Current research believes that the cellular network & lacunocanalicular porosity if responsible for mechanosensing and mechanotransduction

8 What load/strain does the cell see? Klein-Nulend et al. examined cell signaling following mechanical stimulation in cell culture osteocytes were more responsive than osteoblasts fluid flow had more of an effect than intermittent hydrostatic compression

9 Hypothesis Klein-Nulend et al. and Cowin et al. hypothesized: The prime mover for bone adaptation is the strain-driven motion of interstitial fluid through the canaliculi and along osteocyte processes, which is sensed and transduced by osteocytes.

10 Interstitial Fluid Flow

11 Cartoon showing potential ways that an osteocyte may sense fluid flow shear stress. (A). Fluid flow shear stress could perturb tethering elements between the canalicular wall and the cell membrane. (B). Fluid flow shear stress may also affect the cell body, causing cell deformation. (C). Fluid flow may perturb primary cilia leading to mechanosensation. Both matrix and cell deformation are also proposed to play a role in osteocyte mechanosensation. BoneKEy-Osteovision (2006) 3, 7 15

12 Fluid Shear Stress Studies have shown in vitro and in vivo that fluid flow is a mechanical stimuli for bone cells Fluid shear stress is more effective than mechanical stretching on bone cells A 4 point bending study found the rate of displacement to be proportional to fluid force

13 Fluid Shear Stress Fluid flow is not only important for mechanotransduction, but also for maintenance of metabolic activity in osteocytes Fluid flow results in 2 types of stimuli: fluid shear stress (drag) streaming electric potentials

14 OC OC LC

15 OC OC OB

16 OC OC OC LC

17 OC OC LC

18 OC OC

19 OC LC

20 Fatigue OC OC

21 Fatigue OC OC OC OB

22 Fatigue OC OC OC OB OC OC LC

23 Stress Fractures

24 Osteocyte Primary Cilium Malone A M D et al. PNAS 2007;104: Hoey et al. FEndo 2012;3(75): 1-11

25 Learning Objectives Review how cells sense strain on a molecular level Discover how research is done to determine the cells ability to sense strain Explain how cells sense strain on a cellular level Describe the role of fluid shear stress in use, overuse, and disuse of bone Describe the events in bone maintenance during fatigue Describe the primary cilium and its role in mechanosensing