1. Bone: Normal Physiology and Response to Injury Wongworawat August 3, 2010

2. Structure Cortical vs. Trabecular Woven vs. Lamellar Vascular supply –Nutrient artery—intramedullary –Periosteal –Periarticular plexus

3. Extracellular Matrix Mineral: 2/3 –Hydroxyapatite Ca 10 (PO 4 ) 6 (OH) 2 Organic –Type I collagen: 90% –Noncollagenous protein: 10% Osteocalcin, most abundant Proteoglycans Others

4. Collagen Problems OI: Type I collagen Scurvy: Ascorbic acid dependent prolyl hydroxylase and lysyl hydroxylase Ehlers-Danlos: Lysyl oxidase for crosslinking Urinary detection of turnover: pyridinoline, telopeptide, and hydroxyproline

5. Bone Cells Osteoblasts –Receptor for PTH –Roles Form bone Regulate osteoclasts –Lipoprotein receptor-related protein 5 (LRP5) Transmembrane protein for osteoblast proliferation regulation Signaling important for maintenance of bone mass

6. Bone Cells Osteoblast differentiation –Stem cell –Mesenchymal stem cell –Osteoprogenitor –Pre-osteoblast –Mature osteoblast –Osteocyte –Cell deth

7. Osteoblastic Problems Fibrodysplasia ossificans progressiva –Activating mutation in BMP receptor ACVR1 Cleidocranial dysostosis –Loss of runx 2 gene (formerly CBFA 1) –Runx 2: transcription factor, “master regulator” of osteoblast differentiation

8. Osteoclasts Lineage: related to hematopoietic cells, macrophages Receptors –Calcitonin –RANKL, (osteoprotegrin) –Integrin Half-life: 10 days

9. Form and Function Remodeling –Trabecular –Cortical Molecular coupling –PTH –RANKL –BMP

10. Mechanical Regulation Wolff’s Law

11. Mechanical Properties Anisotropic –Stronger in compression than tension Viscoelastic –Higher stiffness and strength at higher loading rates

12. Aging Osteoporosis: 2.5 SD < young standard Increase in both inner and outer diamters More anisotropy

13. Bone Injury and Repair Osteonecrosis Fracture Fixation Adjunctive therapies

14. Osteonecrosis Histo changes 10-14 days after event Empty lacunae MRI findings Bone remodeling: creeping substitution –Vascularization from fibrous tissue –Differentiation of bone cells –Cutting cones –Remodeling

15. Fracture Healing External factors –Micromotion: endochondral ossification –Rigid fixation: direct intramembranous ossification

16. Fracture Healing Inflammatory response Cell differentiation –sox9 upregulates cartilage genes (col2) –Hypertrophic chondrocytes: type X collagen Ossification Remodeling

17. Chondrogenesis Pathology Camptomelic dysplasia: sox9 mutation Cleidocranial dysplasia: runx2 mutation Multiple epiphyseal dysplasia (MED): cartilage oligomeric matrix protein (COMP) Diastrophic dysplasia: sulfate transport protein

18. Fixation Biomechanics Intramedullary device Plates –Rigidity: thickness 3 External fixation –Rigidity Pin diameter, number, bone to rod distance, pin group separation, ½ pins separated 45°

19. Bone Grafts Osteoconductive Osteoinductive Osteogenic Gold Standard: Autograft

20. Allograft Structural Particulate Demineralized

21. Minerals and Other Calcium sulfate Tricalcium phosphate ceramics Calcium phosphate cements Polymers

22. BMP TGF- β family Bind cell curface receptors –Serine/threonine kinase receptors Phosphorylate SMADs SMADs translocates into nucleus to activate genes for osteoblast differentiation

23. Adjunctive Therapies Inductive coupling (magnetic) –Upregulation TGF-β1, FGF-2, BMP Capacitative coupling (electrodes) –Transmembrane calcium translocation –Upregulation of TGF- β1, BMP Ultrasound –Increased TGF- β1, PGE2, PDGF