Chapter 43: Structure & Function of the Musculoskeletal System

Bone Structure and Function

• Bones provide body form, support tissues, and enable movement through muscle attachment.
• Bone marrow contains mesenchymal stem cells (MSCs) that generate bone, cartilage, and fat cells.
• Marrow cavities store hematopoietic stem cells, which form blood and immune cells; in adults, blood cells originate in the skull, vertebrae, ribs, sternum, shoulders, and pelvis.
• Bones store minerals like calcium, phosphate, carbonate, and magnesium, which is key for cellular mechanisms, hormone homeostasis, and immune function.

Elements of Mature Bone Tissue

• Osteoblasts synthesize collagen and proteoglycans, stimulate bone formation, and are involved in osteoclast activity.
• Osteocytes maintain bone matrix, act as mechanoreceptors, and influence osteoblasts and osteoclasts.
• Osteoclasts resorb bone and play a major role in mineral homeostasis.
• Collagen fibers provide support and tensile strength to the bone matrix.
• Proteoglycans control the transport of ionized materials through the matrix.
• Bone morphogenic proteins (BMPs) induce cartilage, bone, tendon, and ligament formation and repair.
• Glycoproteins like sialoprotein promote calcification, while osteocalcin inhibits calcium phosphate precipitation and promotes bone resorption.
• Minerals, especially calcium (regulated by vitamin D), lend rigidity and compressive strength.
• Phosphate balance and alkaline phosphatase are required for proper bone mineralization.
• Vitamins D and K assist with the differentiation and mineralization of osteoblasts and increase bone calcification, respectively.

Bone Formation

• Bone begins forming during embryonic development when mesenchymal stem cells differentiate into chondrocytes or preosteoblasts.
• Endochondral ossification: Mesenchymal stem cells differentiate into chondrocytes → form a mineralized cartilage scaffold for osteoblast formation (long bones)
• Intramembranous ossification: Mesenchymal stem cells directly differentiate into osteoblasts without a cartilage framework (skull and flat bones)

Factors Influencing Bone Formation, Maintenance, and Remodeling

• Bone morphogenic proteins (BMPs) initiate precursor cells into osteoblasts.
• BMP signaling involves TGF-β signals and Smads to regulate osteoblast formation, function, and maintenance.
• WNT genes are protein-signaling factors crucial for musculoskeletal development.
• WNT signaling regulates osteoblast and osteoclast production, bone mass, fracture healing, bone remodeling, and some bone diseases.
• Transforming growth factor-beta (TGF-β) regulates bone formation and various cellular processes.
• Platelet-derived growth factor (PDGF) increases the number of osteoblasts.
• Fibroblast growth factor-2 (FGF-2) increases osteoblast population but not function.
• Insulin-like growth factors (IGFs) increase peak bone mass, decrease osteoblast apoptosis, and maintain bone matrix.
• Smad proteins, bone morphogenic proteins (BMPs), and tumor necrosis factors (TNFs) are cytokines regulating bone metabolism and osteoclast function.
• Osteoprotegerin (OPG) inhibits bone remodeling/resorption by binding to RANKL, suppressing osteoclast formation.
• Receptor activator of nuclear factor κβ (RANK) stimulates differentiation of osteoclast precursors and activates mature osteoclasts.
• BMP antagonists such as Noggin and Gremlin prevent BMP signaling, while Twisted gastrulation acts as either a BMP agonist or antagonist.
• Activin and Inhibin affect both osteoblasts and osteoclasts, helping regulate bone mass and strength.
• Leptin plays a role in bone formation and resorption.
• Wnt antagonists like Dickkopf family (Dkk) and Sclerostin disrupt Wnt signaling, reducing bone mass.
• Nuclear factor of activated κβ cells (NF-κβ) affects embryonic osteoclastogenesis.
• Matrix metalloproteinases (MMPs) help maintain extracellular matrix equilibrium, while A disintegrin and metalloproteinase (ADAM) functions as proteolytic enzymes.
• Cysteine Protease Cathepsin K, expressed by osteoclasts, assists in bone remodeling by cleaving proteins.
• MMP Inhibitors like tetracyclines (especially doxycycline) and bisphosphonates block enzymatic function of MMPs.
• Tissue inhibitors of metalloproteinases (TIMPs) balance the effect of MMPs in maintaining ECM equilibrium.

Bone Cells

• Bones contain osteoblasts (bone-forming), osteocytes (maintain bone), and osteoclasts (bone-resorbing) cells.
• Osteoblasts lay down new bone; after completion they become osteocytes.
• Osteocytes help maintain bone by signaling osteoblasts and osteoclasts to form and resorb bone.
• Osteoclasts are major bone-resorbing cells responsible for remodeling.

Osteoblasts

• Originate from mesenchymal stem cells (MSCs) and initiate bone formation.
• Mature osteoblasts produce inorganic calcium phosphate converted to hydroxyapatite and an organic matrix.
• Osteoblasts and osteocytes control osteoclast differentiation and bone resorption by producing receptor activator of nuclear factor κβ ligand (RANKL) and osteoprotegerin.
• Osteoclasts trigger an osteoblastic response to couple bone formation to bone resorption during bone remodeling which allows skeleton to adapt to environmental challenges and regulate mineral metabolism.
• Responsible for formation of new bone and mineralization of bone matrix, and are responsive to parathyroid hormone (PTH) and produce osteocalcin when stimulated by 1,25-dihydroxy-vitamin D3
• Alter levels of RANKL and osteoprotegerin (OPG) to determine overall osteoclast formation.

Osteocytes

• Most abundant bone cells that are transformed osteoblasts trapped in hardened osteoid.
• Located within lacunae and interconnected by dendritic cytoplasmic processes through canaliculi, forming gap junctions with adjacent osteocytes.
• Act as mechanoreceptors, responding to changes in weightbearing or stress on bone.
• Lying within the lacunae are the osteocyte's primary cilia → primary mechanoreceptors in bone
• Communicate with other bone cells, instruct osteoblasts and osteoclasts about bone formation and resorption, concentrate nutrients in the matrix, regulate bone mass and minerals, and secrete sclerostin and fibroblast growth factor-23 (FGF-23) which influence mineral metabolism.
• Sclerostin inhibits osteoblasts, reducing bone formation; prime target cells of parathyroid hormone (PTH)
• Exchanges between hormones, catalysts, and minerals maintain optimal levels of calcium, phosphorus, and other minerals in blood plasma.

Osteoclasts

• Originate from hematopoietic monocyte-macrophage lineage, are multinucleated bone cells responsible for bone resorption, and migrate over bone surfaces to resorption areas.
• Travel over prepared surfaces to create Howship lacunae as they resorb bone areas, then acidify hydroxyapatite to dissolve it.
• Cell membrane forms deep foldings (ruffled border) to increase surface areas of cells under their borders.
• Bone resorption is achieved with hydrochloric acid, acid proteases (such as cathepsin K), matrix metalloproteinases (MMPs), and the action of cytokines.
• Lysosomes with hydrolytic enzymes assist in digesting vacuoles.
• Bone area is bound through podosomes, or footlike structures, that cluster together along a sealing membrane,
• Osteoclasts retract and loosen from the bone surface under the ruffled border through the action of calcitonin, reverting to the form of their parent cells.
• Osteoclasts maintain serum calcium and phosphorus levels and play a role in the body's immune response.

Bone Matrix

• Made up of extracellular elements of bone tissue: osteoid (35% organic) and minerals (65% inorganic) with 5-8% water.
• Osteoid is predominantly type I collagen with glycosaminoglycans and proteins.
• Inorganic components mainly are calcium and phosphate minerals.

Collagen Fibers

• Osteoblasts synthesize and secrete type I collagen and osteocalcin.
• Collagen molecules assemble into three thin chains to form fibrils, which organize creating gaps for mineral crystal deposition.
• Fibrils interlink and twist to form rope-like fibers, creating supportive strength.
• Collagen is the most abundant macromolecule in the body that can be found in cartilage.
• Cartilage-specific collagens include types II (primary), VI, IX, X, and XI.
• Type IX collagen helps maintain structural integrity of cartilage and resists tensile forces on joint cartilage.
• Proteolytic enzymes degrade type IX collagen in osteoarthritis and rheumatoid arthritis.

Proteoglycans

• Large complexes of polysaccharides attached to a protein core, strengthen bone by forming compression-resistant networks between collagen fibrils.
• Strengthen bone by forming compression-resistant networks between the collagen fibrils and control transport and distribute electrically charged particles.

Glycoproteins

• Carbohydrate-protein complexes of bone that control collagen interactions for fibril formation act play a part in calcification.
• Sialoprotein comprises about 8% of the noncollagenous matrix of bone and easily binds with calcium
• Types include bone sialoprotein, osteocalcin, osteonectin, laminin, albumin, and α-glycoprotein and bone morphogenic proteins (BMPs).
• Osteocalcin is a calcium-binding protein that inhibits calcium phosphate precipitation and plays a part in bone resorption.
• Osteonectin is a bone-specific protein that binds selectively to hydroxyapatite and collagen in the bone matrix.
• Bone albumin transports essential elements to and from bone cells within the calcified matrix and maintains osmotic pressure.
• Bone albumin is permanently fixed to bone mineral crystals until resorbed.
• Laminin stabilizes basement membranes in bones and is important in neurite and axon growth.

Bone Minerals

• Mineralization is the final step in bone formation and consists of a formation of hydroxyapatite crystals within matrix vesicles.
• Amorphous calcium phosphate compounds convert to solid hexagonal crystals of hydroxyapatite (HAP).
• Calcium and phosphorus concentrations increase in the bone matrix and precipitate to form dicalcium phosphate dihydrate (DCPD)..
• Remaining phases proceed until insoluble HAP is produced and around 80-90% of HAP is incorporated into the collagen fibers.
• Amorphous calcium phosphate is distributed throughout the bone matrix.

Types of Bone Tissue

• Bone has compact bone (85% of the skeleton) and spongy bone (15%).
• Compact bone is highly organized, solid, and strong; its basic unit is the haversian system.
• Each haversian system in compact bones includes a central canal, concentric layers (lamella), tiny spaces (lacunae), bone cells (osteocytes), and small channels (canaliculi).
• Spongy bone lacks haversian systems; lamellae are arranged in trabeculae which, filled with red bone marrow, form an irregular meshwork pattern determined by stress direction.
• Periosteum: All bones are covered with a double-layered connective tissue called the periosteum. The outer layer contains blood vessels; the inner layer anchors to the bone
• Outer Layer of the periosteum contains blood vessels and nerves; the Inner Layer contains collagenous Sharpey fibers attach tendons and ligaments to the periosteum of bones

Characteristics of Bone

• The human skeleton has 206 bones: axial (skull, vertebral column, thorax, 80 bones) and appendicular (upper/lower extremities, shoulder/pelvic girdle, 126 bones).
• Bone shape is classified as long, flat, short (cuboidal), or irregular.
• Long bones have a diaphysis (narrow midportion) that merges into a metaphysis and epiphysis (broad end).
• Diaphysis consists of compact bone with a marrow cavity containing yellow marrow.
• The broad epiphysis allows weightbearing to be distributed over a wide area.
• Epiphysis is connected to the metaphysis by an epiphyseal plate in children, merging after puberty.
• Flat bones have two plates of compact bone with spongy bone, while short bones are cuboidal with spongy bone covered by compact bone.
• Irregular bones have thin (compact bone) and thick (spongy bone) segments.

Remodeling

• Bone integrity is maintained by bone remodeling, a three-phase process: resorption, and formation
• Osteoclasts and osteoblasts work together as a basic multicellular unit (BMU).
  • Phase 1 (Activation): Stimulus activates programmed osteocyte cell death → distribution of osteocytes provides osteoclasts with information about where to begin resorbing damaged bone
  • Phase 2 (Resorption): Osteoclasts form a "cutting cone" and resorb bone, leaving a resorption cavity by attaching to bone matrix and releasing lysosomal enzymes. -Phase 3 (Formation): Osteoblasts line walls of resorption cavity and lay down new bone
• Successive layers (lamellae) in compact bone are laid down until the resorption cavity is reduced to a narrow haversian canal around a blood vessel after 4 to 6 months.

Repair

• Microscopic bone injuries or fractures heal by the same stages.
  • Hematoma formation: Vessels are damaged causing hemorrhage; Fibrin and platelets within the hematoma form a meshwork
  • Procallus formation: Fibroblasts, capillary buds, and osteoblasts move into the wound to produce procallus which include cartilage
  • Callus formation: Osteoblasts in the procallus form membranous that increase the phosphate content and calcium to harden the callus
  • Replacement: Basic multicellular units of the callus replaced with lamellar or trabecular.
  • Remodeling: Bone is remodeled to size and shape of bone before injury; this final stage of healing is vital
• Healing depends on severity, type/amount of bone, blood supply, hormones, and treatment.
• Hematoma forms within hours; procallus forms within days; callus forms within weeks; modeling takes years.

Labs related to Muscle Mass

• Serum creatine kinase (CK) concentration is One of the most useful tests, CK is found in large quantities in the muscle fibers, and when these fibers are diseased or damaged, CK leaks into the serum.
• Myoglobin is detectable in the urine after acute muscle damage caused by crush injury, ischemic disorders, extreme exertion, and some inherited diseases.

Types of Joints

• Joints (articulations) are sites where two or more bones meet responsible for joint stability and mobility
• Classified by their degree of movement: synarthrosis (immovable), amphiarthrosis (slightly movable), diarthrosis (freely movable)
• Classified by CONNECTIVE TISSUE structures that hold the joints together: fibrous, cartilaginous, synovial

Fibrous Joints

• Bone united directly to bone by FIBROUS connective tissue making them synarthrosis or immovable joints that can have movement based on distance between the bones and flexibility
• Subdivided into three types:
  • Suture: Dense fibrous tissue in skulls of young children
  • Syndesmosis: Two bony surfaces are united by a ligament or membrane (radius and ulna; or tibia and fibula) that allows some movement.
  • Gomphosis: Special type of fibrous joint in which a conical projection fits into a complementary socket and is held there by a ligament (teeth).

Cartilaginous Joints

• Bone united by cartilage:
  • Symphyses: bones united by fibrocartilage like pubic symphysis and intervertebral disks that allow slight movement.
  • Synchondroses: bones are united by hyaline cartilage (joints between ribs and sternum) with slight movement.

Synovial Joints (Diarthrodial)

• Freely movable joints that may be uniaxial, biaxial, or multi axial according to the shapes of the bone ends
• Enable body movements that are circular or angular.
• One bone is usually stable and serves as an axis for the motion of the other bone.

Parts of the Joint

• A joint is where two or more bones meet, and the function is to provide stability and mobility to the skeleton.
• Tendons allow a short muscle to exert power on a distant joint
• Synovial joint consists of:
  • A fibrous joint capsule (articular capsule): connective tissue, Sharpey fibers attach capsules to periosteum, reinforced by ligaments and tendons, and richly supplied with nerves, blood vessels, and lymphatic vessels
  • A synovial membrane (synovium): smooth, delicate inner lining of the joint capsule composed of subintima and intima cells; vascular subintima merges with the fibrous joint capsule with loose tissue; intima consists of type A ingesting debris, and Type B secreting hyaluronic acid.
  • A joint cavity (synovial cavity): A fluid-filled space between the articulating surfaces which fills the joint cavity and lubricates the joint surface and Loss of synovial fluid leads to rapid deterioration of articular cartilage.
  • Articular cartilage: (layer of hyaline cartilage) which covers and pads the articulating bony surface with strength and biological properties because of the network of collagen fibers that reduce friction in the joint and to bear weight
  • Bursae: Synovial fluid fills the small sacs lined with a membrane and cushion tendons and muscles
• Acute bursitis occurs primarily in the middle years and is often caused by trauma.

Pain Insensitivity in Joints

• Normal articular cartilage has no blood vessels, lymph vessels, or nerves; it's insensitive to pain and regenerates slowly.

Muscle Contraction

• Myofibrils are the functional units of muscle contraction.
• Skeletal muscle requires a constant supply of ATP and phosphocreatine, necessary substances to fuel muscle contraction and calcium transport
• Muscle contraction is a four-step process: excitation, coupling, contraction, and relaxation
  • Excitation: Action potential spreads from nerve terminal, electrical impulse in the muscle fiber membrane, and release of calcium from the sarcoplasmic reticulum
  • Coupling: Calcium ions migrate to myofilaments when the muscle is at rest freeing the actin and allowing binding with myosin
  • Contraction: Calcium ions combine with troponin with the thin filament actin then slides toward the thick filament myosin in a complex, ATP is released when crossbridges attach, and the muscle generates maximal force when actin and myosin have maximal interactions
  • Relaxation: Sarcoplasmic reticulum absorbs calcium, cross-bridges detach, and sarcomere lengthens
• Oxygen Consumption; measured to calculate the metabolic cost of activity.
• RyR1 is predominantly found in skeletal muscle
• RyR2 is found mostly in cardiac muscle
• RyR3 is in the diaphragm, smooth muscle, and brain

Muscle Mechanics

• Each motor unit contracts in an “all or nothing” manner. As the strength, speed, and duration of stimuli increase → the summation of contractions reaches a critical frequency called tetanus.
• Fiber type, innervation ratio, muscle temperature, and muscle shape influence contraction.
• Tetanus and duration are achieved more rapidly in type II than in type I muscle fibers.
• Muscles need to be body temperature and muscles with a large cross-sectional area develop greater contractile forces
• A certain amount of elongation that occurs during the swing of a golf club improves contractile force.

Types of Muscle Contraction

• Isometric contraction (static): Muscle maintains constant length as tension is increased
• Dynamic contraction (Isotonic contraction): positive work is shortening and negative work requires less energy.

Minerals Stored in Bone

• Minerals stored in bone include calcium, phosphate, carbonate, and magnesium.
• There are two phases of mineralization within the final step in bone formation: formation of initial mineral deposit (initiation) and proliferation of additional mineral crystals (growth).
• Majority of mineral content in the body is an analog of naturally occurring hydroxyapatite (HSP). Calcium and phosphate undergo chemical changes to render a final product of insoluble Hap. -Sequence of Ca and phosphate compound formation: Ca and phosphate form fluid calcium phosphate compounds and convert to solid hexagonal crystals of hydroxyapatite (HAP); an increased concentration in bone matrix forms dicalcium phosphate dehydrate (DCPD); The remaining phases of bone crystal formation occur until insoluble HAP is produced, and 80-90% of the HAP is incorporated into the collagen fibers; amorphous calcium phosphate (ACP) is distributed throughout the bone matrix.

Muscle Weight

• Muscle constitutes 40-50% of body weight. It is 75% water, 20% protein, and 5% organic and inorganic compounds.