Transcript runx 2
Bone: Normal Physiology and Response to Injury Wongworawat August 3, 2010 Structure • Cortical vs. Trabecular • Woven vs. Lamellar • Vascular supply – Nutrient artery—intramedullary – Periosteal – Periarticular plexus Extracellular Matrix • Mineral: 2/3 – Hydroxyapatite Ca10(PO4)6(OH)2 • Organic – Type I collagen: 90% – Noncollagenous protein: 10% • Osteocalcin, most abundant • Proteoglycans • Others 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 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 Bone Cells • Osteoblast differentiation – – – – – – – Stem cell Mesenchymal stem cell Osteoprogenitor Pre-osteoblast Mature osteoblast Osteocyte Cell deth 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 Osteoclasts • Lineage: related to hematopoietic cells, macrophages • Receptors – Calcitonin – RANKL, (osteoprotegrin) – Integrin • Half-life: 10 days Form and Function • Remodeling – Trabecular – Cortical • Molecular coupling – PTH – RANKL – BMP Mechanical Regulation • Wolff’s Law Mechanical Properties • Anisotropic – Stronger in compression than tension • Viscoelastic – Higher stiffness and strength at higher loading rates Aging • Osteoporosis: 2.5 SD < young standard • Increase in both inner and outer diamters • More anisotropy Bone Injury and Repair • • • • Osteonecrosis Fracture Fixation Adjunctive therapies 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 Fracture Healing • External factors – Micromotion: endochondral ossification – Rigid fixation: direct intramembranous ossification Fracture Healing • Inflammatory response • Cell differentiation – sox9 upregulates cartilage genes (col2) – Hypertrophic chondrocytes: type X collagen • Ossification • Remodeling Chondrogenesis Pathology • Camptomelic dysplasia: sox9 mutation • Cleidocranial dysplasia: runx2 mutation • Multiple epiphyseal dysplasia (MED): cartilage oligomeric matrix protein (COMP) • Diastrophic dysplasia: sulfate transport protein Fixation Biomechanics • Intramedullary device • Plates – Rigidity: thickness3 • External fixation – Rigidity • Pin diameter, number, bone to rod distance, pin group separation, ½ pins separated 45° Bone Grafts • Osteoconductive • Osteoinductive • Osteogenic • Gold Standard: Autograft Allograft • Structural • Particulate • Demineralized Minerals and Other • • • • Calcium sulfate Tricalcium phosphate ceramics Calcium phosphate cements Polymers BMP • TGF- β family • Bind cell curface receptors – Serine/threonine kinase receptors • Phosphorylate SMADs • SMADs translocates into nucleus to activate genes for osteoblast differentiation 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