Musculoskeletal

Basic components of musculoskeletal system

* ---- = structural scaffold
* ----- = connect bone to bone
* ----- = connect muscle to bone
* ------ = drive movement
* ----- = allows directional movement

bones, ligaments, tendons, muscles, joints

Autoinflammatory disease is when there is a problem with the --------, and autoimmune disease is when the problem is with the ---------

innate immune system, adaptive immune system

Bone functions

* ------ framework of body
* ------ = skull, spine, and ribs protect vital organs
* ------- = acts as attachment point for muscles
* storage of ----- such as calcium and phosphorous
* blood cell formation in the bone marrow

support, protection, movement, minerals

Types of bones

* -------
* consists of arms and bones
* epiphysis (ends of bones)
* growth plates/epiphyseal plates
* diaphysis (shaft)… where marrow cavity is located
* ------
* wrists and ankles
* ----
* sternum and skull
* ------
* sacrum

long bones, shot bones, flat bones, irregular bones

\------/----- bone

* exterior part of the bone
* very dense solid bone that resists deformation
* 80% of total bone mass, but small part of bone itself
* very solid and strong

\------

* interior bone, also called cancellous bone or spongy bone
* meshwork that provides mechanical strength
* very light and strong

compact/cortical, trabecular

Bone cell types

* ----- = mesenchymal stem cells that give rise to all cells
* ------ = produce and maintain cartilage matrix, and the only cell type present in cartilages
* ------ = synthesize bone matrix, essential for building bone
* ------ = mature osteoblasts embedded in matrix they secrete, they maintain the bone, used to be osteoblasts but have now embedded themselves in the bone matrix
* ------ = essentially bone macrophages, as they reabsorb and remodel the bone
* ------ = inactive flattened osteoblasts that cover bone surfaces, can reactivate if more bone needs to be made

osteochonroprogenitor cells, condrocytes, osteoblasts, osteocytes, osteoclasts, bone lining cells

Organic components of bone matrix

* called osteoid, composed of ---------- and other proteins made by osteoblasts

type I collagen

inorganic components of bone matrix

* almost entirely composed of ----- and -------- that form crystals known as ---------
* early bone is made up of osteoid protein, but over time is mineralized by calcium and phosphorous to harden the bone

calcium, phosphorous, hydroxyapatite

Mineralization of bones

* as bone develops the matrix transitions from largely protein based ----- to a mineral based ------ composition
* this occurs as calcium and phosphorous are added to the osteoid
* this process produces the characteristic solid and dense bones

osteoid, hypoxyapatite

Osteogenesis/ossification

* the process of developing bones
* FIVE important factors needed for bone formation = -----

calcium, phosphorous, vitamin D, calcitonin, and PTH

\-------/-------- ossification

* cartilage template is progressively degraded and converted into bone

\-------- /------- ossification

* connective tissue template of mesenchymal cells condenses, and cells begin to synthesize bone

endochondral/long bone, intramembranous/flat bones

Two histological patterns of bone formation

* --------
* newly formed immature bone
* osteoblasts produce osteoid rapidly
* haphazard organization of collagen fibers
* ALL BONES IN THE FETUS… replaced later in life
* occurs at fracture sites during rapid osteoid synthesis (patched up quickly to prevent bleeding)
* --------
* characterized by highly organized parallel alignment of collagen into sheets/lamellae
* fiber arrangement produces high tensile strength
* bone is very strong
* virtually all adult bone

woven, lamellar

Bone remodeling

* -----------
* principle that bone adapts to the load placed on it
* athlete dominant arm is stronger than non-dominant, astronauts lose bone mass while in space due to reduced gravity
* bone is constantly being remodeled
* this is needed to maintain ----- homeostasis, repair bone damage, and adapt to changing stress
* ------ form bone, while ----- resorb bone, and these processes need to be coordinated for proper bone health

Wolf’s law, calcium, osteoblasts, osteoclasts

\-------- is the reduction in bone mass due to loss of BOTH osteoid and mineral matrix

* but bone composition is normal (% osteoid and minerals)

osteoporosis

Major types of osteoporosis

* ------ / ---- osteoporosis
* disease of elderly, also called post-menopausal osteoporosis’
* ------
* drug induced
* Long term glucocorticoid, long term smoking, heavy chronic alcohol abuse
* disease induced
* Cushing’s, **Hyperparathyroidism** (increase PTH = inc osteoclast activity), **Multiple myeloma** (plasma cells are in bone, but cancerous may make lytic areas in bone), and **Chronic renal failure** (proper nutrients are no reabsorbed and vitamin D is not being activated by kidney)

primary/senile, secondary

Clinical manifestations of osteoporosis

* silent until fracture occurs, then pain
* Fractures are usually ------ and occur in the ----- and lower ----- spine as a compression fracture, or sacrum as a sacral insufficiency fracture
* leads to loss of height from vertebral collapse, causing spinal curvature (**kyphosis)**
* fractures can also be traumatic, and usually occur in the wrist or hip

spontaneous, lumber and lower thoracic

Osteoporosis diagnosis

* bone mineral density test is used to diagnose
* ----- = mild loss of BMD
* ------- = significant loss of BMD

osteoporosis preventative treatment

* correct the underlying cause and must start before significant bone loss occurs
* proper intake of ------ and ------
* diet and exercise, avoid cigarettes and heavy alcohol

osteopenia, osteoporosis, calcium and vitamin D

\------ is a rare condition caused by a defect in chloride channel gene (CLCN7)

* also called AlberSchonberg disease
* **causes decreased bone resorption by osteoclasts**
* largely affects spine, pelvis, and base of skin
* **dense bones cause pain by pressing on skin and sensory nerves**
* results in characteristic dense bone vertebral bodies called **sandwich vertebrate**

osteopetrosis

\---------- is a reduction in bone mineral matrix due to lack of vitamin D and/or calcium

* **bone composition is abnormal →osteoid is normal but minerals are abnormal**
* results in SOFT BONES prone to fracture
* leg bones deform under weight of body
* occurs most often in children
* **Rickets**
* this disease occurring in children, usually due to vitamin D and/or calcium deficiency
* major causes
* diet = deficiency in vitamin D and/or calcium
* celiac disease = produces secondary osteomalacia due to damaged intestine unable to absorb minerals
* chronic liver or kidney disease = can’t activate vitamin D
* opposite of osteogenesis imperfecta
* normal mineral but loss of osteoid

**osteomalacia**

\------- is a genetic defect in type I collagen

* **bone marrow composition is abnormal → minerals are normal but osteoid/colloid is abnormal**
* results in BRITTLE BONES prone to fracture
* also called Brittle bone disease
* opposite of osteomalacia
* Normal osteoid/colloid, but abnormal mineral matrix

osteogenesis imperfecta

\--------/------ is the death of bone cells due to decreased blood supply (bone is highly vascularized)

* causes localized areas of necrosis with dead bone cells
* results in weak regions of bone that can collapse and fracture, this can lead to degenerative/osteo arthritis
* can occur due to long term corticosteroid use

osteonecrosis/avascular necrosis

\------- is a bone infection, usually from infection from bacteria or fungal

* typical infection symptoms →pain, fever, pus in wound
* may require surgical intervention to clean wound followed by IV ATBs
* can result in necrosis in affected area of bone that is prone to fracture

osteomyelitis

\--------- is accelerated and uncoordinated bone remodeling

* blasts make too much bone in one area, and resorb too much bone in another area
* largely a disease of elderly, and usually affects spine, skull, pelvis, and femur
* causes bone pain and produces deformed bone prone to fracture

Paget’s disease

Benign bone tumors

* often detected as a bump on bone that may slowly grow larger
* ----- = arise from osteoblasts or clasts
* ----- = arise from fibroblasts
* ------ = arise from chondrocytes

osteoma, non-ossifying fibroma, chondroma

Malignant bone tumors

* primary malignant bone tumors are rare
* ------- / ------- = arise from osteoblasts
* -------- = arise from chondrocytes
* ---------- = arise from osteoclasts, and usually borderline
* ------- = largely a bone cancer in children

osteosarcoma/osteogenic sarcoma, chondrosarcoma, Giant cell tumor, Ewing’s sarcoma

Metastatic bone tumors

* the most common tumor is bones is metastatic from other organs
* the most common primary cancers to metastasize to the bone are -----, ----, -----, and -------
* remember….
* lung, liver, bone, brain are most common metastasis sites

prostate, lung, breast, and kidney

\----------- is defined by the loss of cartilage and formation of bone spurs, known as osteophytes

* also called degenerative arthritis
* this is a **wear and tear disorder** of repetitive stress on the joints
* disease incidence increases with age
* this joint is NOT Inflamed = COLD JOINT

osteoarthritis (OA)

The two main pathological findings in OA are

loss of cartilage and formation of bone spurs (osteophytes)

OA affects the spine, hips, knees, feet, and the last two rows of finger joints and thumb joints in hands

* ------ = bony spurs in distal interphalangeal (DIP) joint
* -------- = bony spurs in the proximal interphalangeal (PIP) joint

Heberden’s nodes, Bouchard’s nodes

\-------- is a systemic autoimmune disease with the major symptoms of joint inflammation and pain

* genetic link is moderately strong, and associated with cells containing MHC II immune receptors
* is a progressive chronic inflammatory disorder, but can have flare ups of painful acute inflammation of joints
* symptoms can enter remission but relapse again
* joint is INFLAMED = HOT JOINT

Rheumatoid arthritis (RA)

Clinical features of RA

* almost always affects the joints in the ------- in a ------- pattern
* usually begins in smaller joints then progress to larger joints
* however, lumbar spine is usually not involved
* the primary disease manifestation is inflammatory arthritis, but can progress to issues involving eyes, heart, vessels, and lungs

extremities, symmetrical

Characteristic findings in RA

* ------- is found in plasma of almost all RA patients, but is NOT specific for RA and is seen in other autoimmune diseases
* IgM or IgG autoantibodies against Fc of normal IgG
* -------- is more specific to RA than the RF
* these are autoantibodies against self molecules
* usually diagnostic of RA if found along with inflammatory markers

rheumatoid factor (RF), anti-CCP

Two main pathological findings in RA are

Pannus and bone erosions

Mechanisms of immune-mediated joint damage in RA

* classic RA pattern shows inflammation of the synovial membrane with inflammatory exudate and cells
* immune cells are present (B and T lymphs, macrophages, neutrophils
* inflammation causes synovial cells to proliferate and cover surface with ------, an inflammatory membrane
* immune cells and osteoclasts in pannus secretes enzymes that destroy cartilage and erode underlying bone leading to -----

pannus, bone erosions

\----------- is a group of conditions that all result in spinal arthritis

* all of these disorders are SERONEGATIVE for rheumatoid factor and anti-CCP

spondyloarthropathy

type of spondyloarthropathy

* formerly called Reiter’s syndrome
* this is arthritis that occurs in response to an infection, BUT no directly caused by the microbe, **but rather the immune response to the infection**

reactive arthritis

type of spondyloarthropathy

* 3% of Crohn’s patients develop spinal arthritis

Crohn’s disease

Type of spondyloarthropathy

* 20% of people with autoimmune skin disease psoriasis develop spinal arthritis

Psoriatic arthritis

type of spondyloarthropathy

* Spinal arthritis
* Usually presents late teens and mostly in men, highly associated with tissue type HLAB27
* Causes fusion of vertebral bodies resulting in rigid spine and spinal immobility known as **bamboo spine**

Ankylosing spondylosis

Type of arthropathy

* crystals that precipitate out of solution in distal joints spaces due to lower temperatures

crystal-induced arthropathies

Type of arthropathy

* caused by monosodium urate (MSU) crystals
* large collections of MSU crystals are called tophi, which is very common in the big toe and outer ear
* -------- gout = gout with tophi formation
* -------- = caused by calcium pyrophosphate crystals
* Both of these types of gout are caused by abnormalities in metabolism and renal clearance of these components

gout, tophacious, pseudogout

type of arthropathy

* infectious organisms directly triggering arthritis at site of infection
* Lyme disease causes Lyme arthritis
* Tuberculosis
* other systemic infections can seed joint spaces with infectious organisms causing arthritis
* do NOT confuse with reactive arthritis, which is arthritis due to antibodies in response to microbes

infectious arthropathy

Type of muscle disease

* genetic defect in muscle gene dystrophin
* causes progressive weakness beginning in childhood which results in the inability to move, swallow, and breath

muscular dystrophy

Type of muscle disease

* autoimmune attack on skeletal muscles resulting in symmetrical weakness, causing difficulty in climbing stairs, getting up from seated position, and lifting objects overhead
* symptoms progress slowly over weeks to months
* treatment is reduce pain and inflammation

polymyositis

Type of muscle disease

* autoimmune condition that affects both skin and skeletal muscles, much like polymyositis, **but also has rashes on the face and hands**
* can affect young children (**juvenile dermatomyositis)**
* symptoms and treatment the same as polymyositis

Dermatomyositis

Type of muscle disease

* relatively common condition of people over 60
* characterized by inflammatory muscle pain (myalgia) and weakness, particularly in shoulder and hips

Polymyalgia rhematica (PMR)

Connective tissue is composed of collagen, elastin, and other glycoproteins that form the --------- that surrounds all organs and tissues

extracellular matrix (ECM)

Connective tissue disorder

* compromises 13 genetic mutations involving connective tissue, but most often affects genes for different types of collagen
* most mutations result in
* **hypermobility of joints**
* **hyperextensible skin**
* **thin and fragile skin**
* some mutations have increased risk of heart valve disease and/or arterial rupture
* not as serious as Marfan’s syndrome
* most often affects females, lifespan can vary from near normal to reduced depending on genetic mutation

Ehlers Danlos syndrome (EDS)

Connective tissue disorder

* somewhat common disease caused by the gene mutation in connective tissue protein fibrillin-1
* autosomal dominant inheritance, severity is variable depending on the gene mutations
* Fibrillin-1 maintains the structure of connective tissue, particularly elastic tissue in vessels, tendons, and ligaments
* anomalies from Fibrillin-1 gene defect
* tall and thin with long arms and legs
* long thin finger and toes
* anomaly in sternum
* eye problem including retinal detachment
* aorta and heart valve defects are the most serious complications
* usually reduced lifespan due to aortic rupture and other cardiac problems

Marfan syndrome (MFS)

All --------- are characterized by autoantibodies and/or autoreactive T cells to self-antigens

* most largely affect one tissue or organ, but all display some level of systemic pathology

autoimmune diseases

Do not confuse autoimmune diseases with the recently described auto-inflammatory diseases

* auto-inflammatory present with systemic symptoms like autoimmune diseases, but there are **NO ------- or ---------**
* defect are mutations of intracellular immune sensor molecules in the innate immune cells
* these defective cells target healthy self-tissue by mistake
* causes intense periods of inflammation resulting in fever, rash, and joint swelling

autoantibodies or autoreactive T cells

All of these are systemic --------- diseases

* polymyositis and dermatomyositis
* rheumatoid arthritis
* vasculitis
* Inflammatory Bowel disease (Crohn’s and colitis)
* Autoimmune atrophic gastritis
* grave’s disease
* hashimoto’s thyroiditis
* Addison’s disease
* type 1 diabetes
* psoriasis
* systemic sclerosis
* multiple sclerosis
* myasthenia gravis
* sarcoid

autoimmune

This is the prototype autoimmune disease with highly heterogenous disease manifestations and activity…patients are like snowflakes

* often called Lupus due to the wolf-like rash around the face and eyes
* chronic condition with relapsing and remitting disease activity
* genetic association with specific MHC II genes

Systemic lupus erythematous (SLE)

major manifestations of SLE

* -------- (inflammatory)
* ------- (membranous glomerulonephritis)
* unique…. immunofluorescence of kidney biopsy shows full house pattern of glomerulonephritis where all immune markers are present
* --------- (purpura)
* ------ (malar rash)

arthritis, nephritis, vasculitis, class lupus rash

classical pathological findings for SLE include ---------- to DNA and DNA associated molecules

* detected by immunofluorescence microscopy

anti-nuclear antibodies

Mechanism of tissue injury in SLE includes ------ deposited in tissue can activate ------ which recruits and activates innate immune cells that cause tissue damage

autoantibodies, complement