MUSCULOSKELETAL SYSTEM

Functions of the Musculoskeletal System:

- Framework for the attachment of muscles, tendons, and ligaments
- Protects and maintains soft tissues in proper position
- Provides stability for the body and maintains the body’s shape
- Storage reservoir for calcium
- Formation of blood cells in the hematopoietic connective tissue in central cavity of bones

Components of the Musculoskeletal System: muscles, bones, cartilage, joints, bursae, tendons, ligaments
1. Muscles
a. Skeletal muscle – voluntary, striated
b. Smooth muscle – involuntary
c. Cardiac muscle – involuntary, striated
2. Bones
- 30% organic material (bone cells, blood vessels, nerves) and 70% salt deposits (calcium, phosphate)
- Classified as long, short, flat, or irregular
- 2 types of mature bones:
o Cancellous (spongy) bone
 Found in interior of bones, composed of trabeculae
 Considerable tensile strength and weight-bearing properties
 Not penetrated by blood vessels; nourished by diffusion through canaliculi
o Compact (cortical) bone
 Densely packed, calcified intercellular matrix
 Found along the lines of stress on long bones and forms a protective shell on others
 Distribution of blood in the cortex occurs through the haversian and Volkmann canals
- Bone marrow – cells involved in blood cell formation (red marrow) and fat cells (yellow marrow)
- Bone cells:
o Osteoprogenitor cells
 Undifferentiated cells that differentiate into osteoblasts after stimulation by growth
factors
o Osteoblasts
 Bone-building cells that synthesize and secrete the organic matrix of bone
 Participate in the calcification of the organic matrix
 Express cell surface receptors that bind to hormones (PTH, vitamin D, estrogen),
cytokines, and growth factors
o Osteocytes
 Mature bone cells that function in the maintenance of bone matrix
 Play an active role in releasing calcium into blood
o Osteoclasts
 Cytokines (IL, TNF, CSFs) and growth factors crucial to osteoclast differentiation
 Phagocytic cells responsible for the resorption of bone matrix
 Releases calcium and phosphate from bone
 Increased by PTH, reduced by calcitonin & estrogen
3. Cartilage – 3 types
a. Elastic cartilage – allows flexibility
b. Hyaline cartilage – at ends of bones; provides support against shock
c. Fibrocartilage – intermediate between dense connective tissue & hyaline cartilage
4. Joints – 2 types
a) Diarthrodial joint
o Freely movable, although movements differ
o Fibrous joint capsule surrounds and supports the joint where ends of the bones meet
 oJoint capsule consists of an outer fibrous layer and an inner membrane (synovium)
 Synovium secretes synovial fluid which lubricates the joint
 Normal synovial fluid is clear or pale yellow, does not clot
 Well-developed vascular supply to the synovium
o Bony surfaces of joints are covered by articular cartilage
 Nourished by the diffusion of substances in the synovial fluid
 Regeneration of cartilage is slow
o Bursae prevent friction on a tendon
 Sacs formed by synovial membranes
 Occur in areas where pressure is exerted b/c bones are physically close together or
where a tendon runs over a bone
 Bursitis – inflammation of bursae
o Ex: hands, hip, knee, shoulder, elbow
b) Synarthrodial joint
o Bones held together by connective tissue, cartilage, ligaments, etc.
o Lack a joint cavity; immobile
o Ex: skull bones, ribs, intervertebral disks
5. Tendons
- Bundles of collagen fibers that attach the muscles to the bones; relatively inextensible
- Transmit force generated by the contracting muscle to the bone and move the bone
- Tendonitis – inflammation of the tendon
6. Ligaments
- Strong fibrous connections between bones
- Allow and limit joint movement
- Exposure to excess stress causes tearing, which is extremely painful and accompanied by swelling

Bone Formation and Metabolism

- Exercise & weight-bearing – stimulates osteoblast activity
- Diet – Calcium deficiency during adolescence will result in bones less dense than optimum later in life. Most of the
calcium present in bones in an individual’s lifetime is deposited before age 20.
- Hormonal Control
o Estrogen, testosterone, and growth hormone
 Enhance osteoblast activity & bone growth
o Parathyroid Hormone (PTH)
 Prevents serum calcium levels from falling below normal physiologic concentrations
 Prevents serum phosphate level from rising above normal physiologic concentrations
 Regulated by negative feedback of increased serum calcium levels
 Functions:
 Initiate calcium & phosphate release from bone
 Conservation/reabsorption of calcium by the kidneys
 Urinary excretion of phosphate
 Ensures that increased release of phosphate from bone during mobilization of calcium
does not produce an elevation in serum phosphate levels
 Increases in calcium and phosphate levels  crystallization in soft tissues
 Enhanced intestinal absorption of calcium through activation of vitamin D
o Calcitonin
 Lowers blood calcium levels
 Inhibits the release of calcium from bone
 Major stimulus for calcitonin synthesis & release is an increase in serum calcium levels
 Functions:
 Causes calcium to be sequestered in bone cells
 Inhibits osteoclast activity
  Reduces the renal tubular reabsorption of calcium & phosphate
o Vitamin D
 Must be converted to physiologically active compounds
 Sources: intestinal absorption and skin production
 Increases intestinal absorption of calcium and promotes the actions of PTH
 Stimulated by PTH & prolactin, inhibited by calcitonin

Bone Remodeling
- Osteoblasts and osteoclasts act in coordination and are considered the functional unit of bone, as the basic
mulcicellular unit.
- Processes of boen formation/resorption are tightly coupled, and their balance determines skeletal mass.
- Once skeletal growth has attained its adult size after bone modeling, the breakdown/renewal of bone
responsible for skeletal maintenance is called bone remodeling.
- Mature bone is made up of osteons or units of concentric lamellae and the haversian canal they surround.
- Length of one bone remodeling cycle is approximately 4 months.
- Ideally, the replaced bone should equal the resorbed bone.
- Control of bone metabolism and remodeling:
o RANKL – expressed by osteoblasts & their precursors; necessary for osteoclast differentiation & function
o RANK – receptor for RANKL; expressed on osteoclasts & their precursors
o Osteoprotegerin (OPG) – inhibitor receptor for RANKL; protects against bone loss
o RANKL + RANK  osteoclast differentiation & proliferation
o RANKL + OPG  blocks the action of RANKL
o Dysregulation of RANKL/RANK/OPG pathway plays a prominent role in pathogenesis of bone diseases
(i.e. osteoporosis, RA).
o Estrogen stimulate OPG production.
o Glucocorticoid exposure, which can cause steroid osteoporosis, enhances RANKL expression and
suppression OPG levels.
- Bone remodeling cycle:
o Bone Resorption
 Osteoclasts remove organic (protein matrix) and inorganic (mineral) components
 Creats a tunnel-like space in the osteon
 Soluble factors released during resorption aid in recruitment of osteoblasts to the site
o Bone Formation
 Osteoblasts begin to deposit the organic matrix (osteoid) on the wall of the osteon canal.
 PTH has minimal or no direct effect on osteoclasts.
 Once the osteoblast receives appropriate signal, it releases RANKL
- Metabolic bone disorders have their origin in the bone remodeling process.
 DISORDERS OF THE MUSCULOSKELETAL SYSTEM

Joint Injuries
- Strains
o Trauma to a muscle or tendon caused by mechanical overloading
o Usually occurring when it is stretched beyond normal limits
o May involve tissue tears or ruptures
o Inflammation occurs with injury
o Manifestations: pain, stiffness, swelling
- Sprains
o Trauma to a joint, usually related to a ligament injury from abnormal or excessive movement
o Leads to inflammation, swelling, and pain
o Manifestations: pain, rapid swelling, heat, disability, discoloration, limitation of function
- Healing
o Accomplished by fibroblasts from the inner tendon sheath or from the loose connective tissue that
surrounds the tendon
o Capillaries supply the fibroblasts with materials needed to produce large amounts of collagen
- Treatment
o Elevation of part followed by local application of cold
o Compression helps reduce swelling and provides support
o Immobilization

Hip Fractures
- The hip is a ball and socket joint in which the femoral head articulates in the acetabulum
- Major public health problem particularly in the elderly
- Results in hospitalization, disability, and loss of independence
- Incidence increases with age, higher in women than men, higher in white women than nonwhite women
- Risk factors: excessive consumption of alcohol & caffeine, physical inactivity, low body weight, tall stature, use of
psychotropic drugs, residence in an institution, visual impairment, dementia, osteoporosis
- Most result from falls
- Generally a fracture of the proximal femur
- Location of a hip fracture is important in terms of blood flow to the femoral head, which receives its blood
supply from vessels that course proximally up the femoral neck
- Diagnosis: clinical findings, standard radiographs
- Goal of treatment: return to preinjury level of function asap

Fractures
- Discontinuity of bone
- Most common type of bone lesion
- Occurs when more stress is placed on the bone than it is able to absorb
- 3 categories: sudden injury, stress/fatigue fractures, pathologic fractures
- Classification:
o Location – proximal, midshaft, distal
o Type
 Communication with the external environment
 Compound (open) Fracture
o Bone fragments have broken through the skin
o Complicated by infection, osteomyelitis, delayed union, or nonunion
 Closed fracture
  Degree of break in continuity of bone
 Greenstick Fracture
o Partial break in bone continuity
o Seen in children
 Character of the fracture pieces
 Comminuted Fracture – more than 2 pieces
 Compression fracture – in the vertebral body; involves 2 bones crushed together
 Impacted fracture – fracture fragments are wedged together
o Direction/pattern of the fracture line
 Transverse Fractures
o Caused by simple angular forces
o Not likely to become displaced or lose its position after restoration to normal
anatomic position (reduction)
 Spiral Fractures & Oblique Fractures
o Results from a twisting motion or torque
o Often unstable and may change position after reduction
- Effects of bone fracture:
o Bone cells die when a bone breaks
o Bleeding occurs around the site and into the soft tissues surrounding the bone
o Inflammatory reaction follows the break  WBCs & mast cells accumulate  increased blood flow to
are  phagocytes and removal of dead cell debris begin  fibrin clot (fracture hematoma) forms at the
break  fibrin clot reabsorbed
o Osteoblastic activity immediately stimulates  immature new bone (callus) formed  new bone cells
are slowly remodeled to form true bone
o Healing takes several weeks to months
o Healing can be delayed or impaired if the fracture hematoma or callus is disrupted before true bone is
formed, or if the new bone cells are disrupted during calcification and hardening
- Manifestations:
o Pain, tenderness, swelling, loss of function, deformity of affected part, abnormal mobility
o 3 types of deformities in long bones: angulation, shortening, rotation
o Temporary loss of nerve function  area numb, muscles flaccid
- Complications: loss of skeletal continuity, injury from bone fragments, pressure from swelling and hemorrhage,
involvement of nerve fibers, development of fat emboli
- Diagnosis: history, physical manifestations, x-ray, soft tissue injury
- Treatment:
o Goals: reduction of fracture, immobilization, preservation & restoration of the function of injured part
o Reduction and internal fixation
o Immobilization (splints, casts, traction) and external fixation
 Traction
 Achieves immobility, maintains alignment of the bone ends and reduction
 A pulling force applied to an extremity while a counterforce pulls in the opp. direction
 Goals:
o Correct and maintain the skeletal alignment of bones/joints
o Reduce pressure on a joint surface
o Correct/lessen/prevent deformities (i.e. contractures, dislocations)
o Decrease muscle spasm
o Immobilize the fracture site to promote healing
 Types:
o Manual – pull exerted by the hands
o Skin – pulling force applied to skin and soft tissue
o Skeletal
 Pulling force applied directly to bone
  Use of pins, wires, tongs
 Can be used for long periods w/ large amounts of weight
 Used for fractures of femur, humerus, cervical spine
o Limb-lengthening systems
o Exercises, active ROM
Osteopenia
- Definition: Reduction in bone mass greater than expected for age, race, or sex
- Causes:
o Decrease in bone formation
o Inadequate bone mineralization
o Excessive bone deossification

Osteoporosis
Disease summary #79.

Ankylosing Spondylitis
- Chronic, systemic inflammatory disease of the joints of the axial skeleton manifested by pain and progressive
stiffening of the spine.
- More common in men than in women
- Description:
o Produces an inflammatory erosion of the sites where tendons and ligaments attach to bone
o Begins with bilateral involvement of the sacroiliac joints  smaller joints of posterior spine
o Results in ultimate destruction of these joints with ankylosis or posterior fusion of the spine
o Vertebrae take on a squared appearance and bone bridges fuse vertebral bodies together
o Progressive spinal changes usually follow an ascending pattern
o Large synovial joints (hips, knees, shoulders) may be involved occasionally
o Small peripheral joints not usually affected
- Etiology:
o Genetic (90% of patients possess HLA-B27 antigen) and environmental factors
o (Auto)Immune response
- Manifestations:
o Usually begin in late adolescence or early adulthood
o Periods of exacerbations & remissions common
o Persistent or intermittent low back pain
o Lumbosacral pina, discomfort in the buttocks and hp areas
o Prolonged stiffness after periods of rest
o Walking or exercise may be needed to provide comfort
o Loss of motion in the spinal column
o Lumbar lordosis  loss of lumbar lordosis  kyphosis of thoracic spine & extension of neck
o Acute anterior uveitis
o Abnormal weight bearing  degeneration/destruction of hips
o Peripheral arthritis
o Weight loss, fever, fatigue
o Osteoporosis
o Fusion of costovertebral joints  reduced lung volume
- Diagnosis: history, PE, x-ray, elevated ESR
- Treatment:
o Proper posture and positioning o Maintaining ideal body weight
o Sleeping on a firm mattress o NSAIDs to reduce inflammation, relieve
o Muscle-strengthening exercises pain, and reduce muscle spasm
o Heat applications or shower/bath o DMARDs
o Swimming o Anti-TNF-alpha therapies
Gout
- Crystal-induced arthropathy caused by monosodium urate deposition
- Gout syndrome:
o Acute gouty arthritis – crystal deposition in joints
o Tophi – accumulation of crystalline deposits in articular surfaces, bones, soft tissue, cartilage
o Gouty nephropathy / renal impairment
o Uric acid kidney stones
- Primary gout used to designate cases in which the cause of the disorder is unknown or an inborn error in
metabolism and is characterized by hyperuricemia and gout.
- Secondary gout may result from treatment for lymphoma/leukemia or from chronic renal disease
- Pathogenesis:
o Elevation of serum uric acid levels
o Uric acid is the end product of purine metabolism
o Causes:
 Overproduction of purines
 Decreased salvage of free purine bases
 Augmented breakdown of nucleic acids as a result of cell turnover
 Decreased urinary excretion of uric acid
o Monosodium urate crystals precipitation in the joint  inflammatory response
o Crystal deposition usually occurs in peripheral areas of the body where the temperatures are cooloer
o Crystals are also chemotactic to leukocytes and activate complement
o Inflammation causes destruction of the cartilage and subchondral bone
o Repeated attacks of acute arthritis  chronic arthritis  formation of tophi
 Most commonly in the synovium, olecranon bursa, Achilles tendon, subchondral bone, extensor
surface of the forearm
 Tophi doesn’t appear until 10+ years after the first gout attack
- Manifestations:
o Often begins at night and may be precipitated by excessive exercise, medications, foods, alcohol, dieting
o Onset of pain abrupt, redness and swelling observed
o Attack may last for days or week
- Diagnosis: monosodium urate crystals in the synovial fluid or tissue sections, serum uric acid levels
- Treatment:
o Goal: termination & prevention of acute attacks, correction of hyperuicemia, consequent inhibition of
further precipiation of sodium urate already in the tissues
o NSAIDs to reduce joint inflammation
o Colchicine, corticosteroids
o Treatment of hyperuricemia is lifelong (allopurinol, uricosuric drugs)

RHEUMATOID ARTHRITIS (RA)

Definition:
- chronic, systemic, noninfectious, progressive, inflammatory disease
- primarily affects the connective tissue of the body, especially synovial membranes of multiple joints
- inflammation invades cartilage and surrounding tissue
- characterized by synotivis (infection of synovium) and joint destruction
- autoimmune disease, immune system recognizes native tissue as foreign and targets them for destruction
- can also affect a wide variety of extra-articular tissue
- affects mostly older women
- one of the most debilitating of all forms in arthritis
- shortened life span if untreated
- many serious complications caused by drug therapy
Causes & Risk Factors:
- genetic
- environment
- hormonal factors (estrogen, pregnancy)
- multifactorial disease
- HLA-DR4, HLA-DR1 within MHC complexes on T-cells
- Antigens from microbes or viruses are suspected of being factors

Cell Interactions that drive RA process:

- CD4 T cells responsible for initiating and sustaining RA
- T cells inappropriately recognize auto-antigens (HLA-DR) on APCs  activating of T-Cell
- Stimulating release of cytokines  macrophages
- T cells stimulate B cells  B cells release rheumatoid factors  immune complexes, more proinflammatory
cytokines that activate macrophages
- Pro-inflammatory cytokines: IL-1, TNF-alpha  degrade cartilage & bone matrix
- Remember: cytokines are both pro-inflammatory & anti-inflammatory, thus their homeostasis is no longer
balanced
- IL -1:
o Activates monocytes (serum) and macrophages (tissue)  inflammation
o Induce fibroblast proliferation  overgrowth of synovial tissue
o Activates chondrocytes  destructive proteolytic enzymes that break down cartilage
o Stimulates osteoclasts (and prevents osteoblasts)  bone resorption
- Major cell types: T cells, macrophages, fibroblasts, plasma cells, endothelium, DCs, neutrophils
- Autoimmune and inflammatory responses both happening at the same time

IL-1B and TNF-alpha: pro-inflammatory cytokines in the rheumatoid joint

- increased concentrations of IL-1 and TNF act to stimulate production of each other 
o degrade cartilage matrix
o increase osteoclasts
o increase adhesion molecules in endothelium 
 neutrophils migration 
 synovial fibroblasts  release IL-8, prostaglandins, IL-6 (acute chronic infl)
- NSAIDs are trying to stop pro-inflammatory cytokines, pannus formation, bone destruction
- COX-2 inhibitors (COX-2), NSAIDs (prostaglandin)
- Both cytokines both upregulate COX-2, PGE, NO, IL-6 (activate innate immune system)
- Both increase expression of adhesion molecules & cytokines & collagenases (chrondrocytes)
- IL-1: TNF, osteoclasts, angiogenic factors
- TNF: IL-1, programmed cell death

Clinical Manifestations:
- Chronic swelling and thickening in symmetric peripheral joints
- ROM limited
- Feet worse than hands
- Rheumatoid nodules (usually located over bony prominences)
- Nonarticular muscular structures
- Systemic disease
- Skin is thin and shiny
- Insidious: malaise, stiffness, joint pain, swollen/warm/tender joints
- Low grade fever, loss of appetite, fatigue, weight loss
- Dryness of eye, mouth, mucus membranes (more advanced)

Diagnosis:
 - Splenomagaly, adenopathy
- Serum abnormalities
o Antibodies to cyclic citrullinated peptide (95%) – definitive
 CCP is 50% sensitive in early part of disease
o 25% ANA positive
o IgG and IgM and ESR high
o Mild to moderate anemia
o WBC normal or slightly elevated, leucopenia
o Platelet counts are elevated
- X-rays
o Earliest changes in wrist and feet
o Narrowing of joint spaces & erosion
- Knee joint fluid examination
o Exceeds 3.5ml in volume
o Translucent to opaque in clarity and yellow to opalescent in color
o High neutrophils and high macrophages – flare
o Glucose level that is less than the patient’s serum glucose concentration
- Morning stiffness, swelling, nodules, RF, x-rays

Non-Pharmalogical Treatment:
- education - splints
- systemic rest - weight loss
- joint rest - apheresis
- exercise - dietary modifications
- heat & cold - PT
- assistive devices

Pharmacologic Treatment:
- Be aggressive in management esp. in early stages (2 year window)
- NSAIDS - Corticosteroids – phase them out
o COX-2 inhibitors - Abatacept
o PPI, H2 blockers - Rituximab
- MTX (methytrexate?) – not used by itself - Sulfasalazine & monocylcline
- TNF-alpha inhibitors – very expensive - Leflunomide
- Hydroxychloroquine sulfate – anti-malarial - Anakinra
agent b/c of anti-inflammatory activity; visual - Combination therapies
loss is a complication - Surgery – when not having results

There is a lot of complications with this disease. Joint deformities and systemic problems. Most common cause of death
is infection, GI disease, respiratory, or renal failure. Many are attributed to complications of therapy.