CHAPTER 1 BASIC SCIENCES Jeremy K. Rush, Dustin Lybeck, Jessica Rivera, and Matthew R. Schmitz CONTENTS SECTION 1 ORTHOPAEDIC TISSUES, 1 SECTION 3 PERIOPERATIVE AND ORTHOPAEDIC Bone, 1 MEDICINE, 78 Cartilage and Joint, 34 Thromboprophylaxis, 78 Muscle, 52 Perioperative Disease and Comorbidities, 84 Tendon, 57 SECTION 4 OTHER BASIC PRINCIPLES, 89 Ligament, 58 Imaging and Special Studies, 89 Neural Tissue and Intervertebral Disc, 59 Biomaterials and Biomechanics, 93 SECTION 2 ORTHOPAEDIC BIOLOGY, 61 TESTABLE CONCEPTS, 107 Cellular and Molecular Biology and Immunology, 61 Infection and Microbiology, 70 SECTION 1 ORTHOPAEDIC TISSUES BONE • These stem cells line haversian canals, endosteum, and periosteum. n Histologic features of bone • Become osteoblasts under conditions of low strain n Types (Fig. 1.1; Table 1.1) and increased oxygen tension • Normal bone: lamellar or mature • Transcription factor RUNX2 and bone • Immature and pathologic bone: woven, more random, morphogenetic protein (BMP) direct more osteocytes, increased turnover, weaker mesenchymal cells to the osteoblast lineage. • Lamellar bone is stress oriented; woven bone is not. • Core-binding factor -1 and -catenin also • α β Cortical (compact) bone stimulate differentiation into osteoblast • Constitutes 80% of the skeleton • Become cartilage under conditions of intermediate • Consists of tightly packed osteons or haversian strain and low oxygen tension systems • Become fibrous tissue under conditions of high • Connected by haversian (or Volkmann) canals strain • Contains arterioles, venules, capillaries, nerves, • Have more endoplasmic reticulum, Golgi apparatus, possibly lymphatic channels and mitochondria than do other cells (for synthesis • Interstitial lamellae: between osteons and secretion of matrix) • Fibrils connect lamellae but do not cross cement • Bone surfaces lined by more differentiated, lines. metabolically active cells • Cement lines define the outer border of an • Entrapped cells: less active cells in resting regions; osteon. maintain the ionic milieu of bone • Nutrition provided by intraosseous circulation • Disruption of the active lining cell layer activates through canals and canaliculi (cell processes of entrapped cells. osteocytes) • Receptor-effector interactions in osteoblasts are • Characterized by slow turnover rate, higher Young’s summarized in Table 1.2. modulus of elasticity, more stiffness • Osteoblasts produce the following: • Cancellous bone (spongy or trabecular bone) • Alkaline phosphatase • Less dense, more remodeling according to lines of • Osteocalcin (stimulated by 1,25dihydroxyvitamin stress (Wolff’s law) D [1,25(OH) D ]) • 2 3 Characterized by high turnover rate, smaller Young’s • Type I collagen modulus, more elasticity • Bone sialoprotein n Cellular biology (Fig. 1.2) • Receptor activator of nuclear factor (NF)- ligand • κβ Osteoblasts (RANKL) • Appear as cuboid cells aligned in layers along • Osteoprotegerin—binds RANKL to limit its activity immature osteoid • Osteoblast activity stimulated by intermittent • Are derived from undifferentiated mesenchymal stem (pulsatile) exposure to parathyroid hormone (PTH) cells 1 2 Basic Sciences Cortical Immature Cancellous Pathologic (giant cell tumor) Haversian canal Cement line Interstitial lamellae Canaliculi Osteocyte CORTICAL BONE DETAIL FIG. 1.1 Types of bone. Cortical bone consists of tightly packed osteons. Cancellous bone consists of a meshwork of trabeculae. In immature bone, unmineralized osteoid lines the immature trabeculae. Pathologic bone is characterized by atypical osteoblasts and architectural disor- ganization. (Colorized from Brinker MR, Miller MD: Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 2.) Table 1.1 Types of Bone MICROSCOPIC APPEARANCE SUBTYPES CHARACTERISTICS EXAMPLES Lamellar Cortical Structure is oriented along lines of stress Femoral shaft Strong Cancellous More elastic than cortical bone Distal femoral metaphysis Woven Immature Not stress oriented Embryonic skeleton Fracture callus Pathologic Random organization Osteogenic sarcoma Increased turnover Fibrous dysplasia Weak Flexible Modified from Brinker MR, Miller MD:Fundamentals of orthopaedics, Philadelphia, 1999, Saunders, p 1. • Osteoblast activity inhibited by TNF-α • Osteocytes (see Fig. 1.1) • Wnts are proteins that promote osteoblast survival • Maintain bone and proliferation. • Constitute 90% of the cells in the mature skeleton • Deficient Wnt causes osteopenia; excessive Wnt • Former osteoblasts surrounded by newly formed matrix expression causes high bone mass. • High nucleus/cytoplasm ratio • Wnts can be sequestered by other secreted • Long interconnecting cytoplasmic processes molecules such as sclerostin (Scl) and projecting through the canaliculi Dickkopf-related protein 1 (Dkk-1). • Less active in matrix production than osteoblasts • Inhibiting sclerostin or Dkk-1 will lead to • Important for control of extracellular calcium and increased bone mass phosphorus concentration Basic Sciences 3 Stem cell Myeloid progenitor Hematopoietic progenitor Pre-osteocytes Monocyte Myocyte Cell-cell fusion Adipocyte Macrophage Fibroblast Chondroblast/ chondrocyte Multi-nuclear osteoclast Osteoblast/osteocyte Osteocytes Chondroblasts Perichondrium Osteoblasts Lacuna Chondrocyte Isogenic group Extracellular matrix Myoblast Adipocyte Stem cell Haversian canal Multipotential Tri- or bipotential Osteoblast daughter cell progenitor cells Chondroblast Fibroblast FIG. 1.2 Cellular origins of bone and cartilage cells. Table 1.2 Bone Cell Types, Receptor Types, and Effects CELL TYPE RECEPTOR EFFECT Osteoblast PTH Releases a secondary messenger (exact mechanism unknown) to stimulate osteoclastic activity Activates adenylyl cyclase 1,25(OH)2 vitamin D3 Stimulates matrix and alkaline phosphatase synthesis and production of bone-specific proteins (e.g., osteocalcin) Glucocorticoids Inhibits DNA synthesis, collagen production, and osteoblast protein synthesis Prostaglandins Activates adenylyl cyclase and stimulates bone resorption Estrogen Has anabolic (bone production) and anticatabolic (prevents bone resorption) properties Increases mRNA levels for alkaline phosphatase Inhibits activation of adenylyl cyclase Osteoclast Calcitonin Inhibits osteoclast function (inhibits bone resorption) 4 Basic Sciences Liberated Proliferation matrix-bound Osteoprogenitor cells growth factors Inhibition of osteoblast activity Mechanical factors BMP hormones Proliferation Sclerostin Osteoclast cytokines and maturation precursor Surface Wnt Active osteoblasts LRP5/6 osteoblasts β-catenin Mediators of osteoclastogenesis Osteoclast Osteocyte Microdamage FIG. 1.3 Paracrine crosstalk between osteoblasts and osteoclasts. (From Kumar V et al, editors: Bones, joints, and soft tissue tumors. In Robbins and Cotran pathologic basis of disease, ed 9, Philadelphia, 2014, Saunders, Fig. 26-5.) • Directly stimulated by calcitonin, inhibited by PTH • Border consists of plasma membrane enfoldings • Sclerostin secreted by osteocytes helps negative that increase surface area feedback on osteoblasts’ bone deposition (Fig. 1.3). • Bind to bone surfaces through cell • Differentially regulated according to mechanical attachment (anchoring) proteins loading, with decreased sclerostin in areas of • Integrin (αvβ3 or vitronectin receptor) concentrated strain • Bone resorption occurs in depressions: Howship • Downregulation is associated with increased bone lacunae. formation (via sclerostin antibody). • Effectively seal the space below the osteoclast • Potential for use in fracture healing, bone loss, • Synthesize tartrate-resistant acid phosphate osseous integration of implants, and genetic bone • Produce hydrogen ions through carbonic diseases via upregulation of sclerostin anhydrase • Osteoclasts • Lower pH • Multinucleated irregular giant cells • Increase solubility of hydroxyapatite crystals • Derived from hematopoietic cells in macrophage • Organic matrix then removed by proteolytic lineage digestion through activity of the lysosomal • Monocyte progenitors form giant cells by fusion enzyme cathepsin K • Function • Signaling • Bone resorption • Have calcitonin receptors, which inhibit • Bone formation and resorption are linked osteoclastic resorption • Stimulated primarily by RANKL binding to • Interleukin-1 (IL-1): potent stimulator of RANK receptor on cell surface osteoclast differentiation and bone resorption • Osteoblasts (and tumor cells) express • Found in membranes surrounding loose total RANKL (Fig. 1.4): joint implants • Binds to receptors on osteoclasts • In contrast, IL-10 suppresses osteoclasts. • Stimulates differentiation into mature n Matrix (Table 1.3) osteoclasts • Organic components: 40% of dry weight of bone • Inhibited by osteoprotegerin (OPG) • Collagen (90% of organic components) binding to RANKL • Primarily type I (mnemonic: bone contains the • Occurs both normally and in certain conditions, word one) including multiple myeloma and metastatic • Type I collagen provides tensile strength of bone disease bone • Denosumab is a monoclonal antibody that • Hole zones (gaps) exist within the collagen fibril targets and inhibits RANKL binding to the between the ends of molecules. RANK receptor • Pores exist between the sides of parallel • Resorption mechanism molecules. • Osteoclasts possess a ruffled (brush) border and • Mineral deposition (calcification) occurs within the surrounding clear zone hole zones and pores. Basic Sciences 5 • Cross-linking decreases collagen solubility and Vit D increases its tensile strength.