Skeletal Pathology and Tumor
Woven vs lamellar bone
What kind of bone does the adult skeleton consist of? Mature lamellar bone
When does woven bone form? Woven bone forms rapidly in response to skeletal injury.
Describe lamellar bone. Collagen fibers are arranged in parallel, and small, uniform osteocytes are scattered through matrix.
Describe woven bone. Osteocytes are more numerous and variable in size, and collagen fibers are not arranged in a lamellar array.
After injury, what eventually happens to woven bone? It is replaced by lamellar bone. Woven bone in adults is abnormal except at tendonous insertions.
Basic Multicellular Unit
T/F Bone is dynamic and constantly remodeling. True; Old bone is resorbed and replaced by new bone.
What is the basic multicellular unit(BMU) of bone. Osteoblasts and osteoclasts.
What is the first step in the remodeling process of bone? How does it begin? Activation; Unclear, but it is implied that signals from osteocyte in response to physical stress (mechanicotransduction).
What is mechanotransduction? Respond to physical strength that signals osteocytes to ACTIVATE remodeling process.
What causes most skeletal diseases? Excessive osteoclastic activity leading to imbalanced resorption.
What is bone modeling? When does it occur? Process that leads to changes in the size and shape of bone. In developing and growing skeleton.
What distinguishes bone remodeling to bone modeling? The key components osteoblasts and osteoclasts are not coupled to each other as in bone remodeling.
What percentage of skeleton is remodeled yearly? 5 - 10%
RANK and RANK-L
Where is RANK-L expressed? (receptor activator of nuclear factor-Kappa B Ligand) Surface of osteoblasts
What stimulates(3) osteoblasts to express RANK-L? PTH, 1,25 dihyroxyvitamin D3, Prostaglandins(PGE2)
In rheumatoid arthritis, osteoclasts erodes subchondral bone. How are these osteoclasts activated? RANKL is produced by activated T-cells(CD4 lymphocytes) in the synovium of joints.
What is osteoprotegrin? Who secretes osteoprotegrin? Function. A secreted decoy receptor for RANK-L. Secreted by osteoblasts. Regulates the maturation/activity of osteoclasts.
What(2) promotes the formation of osteoclasts? What produces these molecules? M-CSF(macrophage colony-stimulating factor) and RANK; Stromal cells and osteoblasts.
What causes the differentiation and maturation of osteoclasts precursors? The binding of RANKL to RANK.
What inhibits OPG? PGE2 and Vit D3
How do osteoclasts communicate with osteoblasts? By releasing anabolic cytokines such as ILGF-1 and TGF-Beta from digested bone matrix.
Name two types of bone fractures. Which is the most common? Traumatic and pathologic; TRAUMATIC
What causes pathologic bone fractures? Weakened bones by disease.
Compare soft tissue injury repair to repair of bone fractures. Both process are similar, except bone requires chondroblasts and osteoblasts to lay down skeletal matrix.
Name the 5 most common causes of delayed healing of bone. 1. infection 2. instability at fracture site 3. Poor bone quality in patients with osteoporosis or genetic disease of skeleton(osteogenesis imperfecta) 4. Remnants of necrotic bone 5. Poor nutrition
What are the phases of bone fracture repair? Inflammatory, Reparative, Remodeling
What is the purpose of the remodeling phase? How long is this process? Cartilage and woven bone are replaced by lamellar bone. Months to years.
What occurs during the reparative phase? How long does the phase lasts? Osteoclasts removes necrotic bone and osteoblasts/chondroblasts produce cartilage and woven bone forming a HARD CALLUS. Several weeks.
What are the important steps of the inflammatory phase of bone repair? How long does this phase last? Angioblasts and fibroblasts produce a soft PROCALLUS that does NOT adequately stabilize the fracture. ~1 week
Name three inflammatory mediators that produce the result in the inflammatory phase of bone repair. Where do they come from? FGF, PDGF, TGF-beta; Hematoma.
Name two types of osteomyelitis. Pyogenic osteomyelitis and Granulomatous osteomyelitis
What is Pott Disease? Vertebral tuberculous osteomyelitis.
What is osteomyelitis? Inflammation of bone and marrow caused by microorganisms.
In osteomyelitis, how do microorganisms typically enter the bone? Hematogenously
Name the most common inciting agent of osteomyelitis. Staphylococcus aureus
In hematogenous osteomyelitis, what determines where bacteria will lodge in the bone? Vascular pattern (loop) at the physis. Neonate-both sides of physis ; Growing plate-metaphysis; Adult skeleton-both sides of physis.
What is a sequestrum? A piece of necrotic bone surrounded by the abscess caused by osteomyelitis.
What in an involucrum? Sleeve of new bone surrounding dead infected bone.
What population gets granulomatous osteomyelitis? Patients w. TB.
Where does granulomatous osteomyelitis most commonly effect? Thoracic and lumbar vertebrae.
How are lesions in granulomatous osteomyelitis spread? Hematogenously or direct extension from pulmonary lesions. Affected verterbrae collapse infecting adjacent bone and tissue.
Osteoptresis falls in the what category of disease? developmental
What is osteopetrosis? Decreased osteoclasts function resulting in decreased resorption during remodeling, >> Sclerosis(hardening) of skeleton.
What happens to the sclerotic bone formed in osteopetrosis? The bones are dense, but abnormally brittle, that they commonly fracture.
What is the most common cause of osteopetrosis? Loss of Carbonic anhydrase II in osteoclasts
Why is carbonic anhydrase important? Carbonic anhydrase acidifies the extracellular environment required for resorption.
Name a recent discovery in the cause of osteopetrosis. Mutation in the gene encoding RANK-L
How can osteopetrosis be treated? Bone marrow transplant
Osteogensis imperfecta falls in what category of disease? developmental, genetic
What is the cause of osteogenesis imperfecta? Genetic disease in the synthesis of Type I collagen due to defect of alpha 1 and 2 chains of collagen.
What is osteopenia? Low bone density
What are symptoms of osteopenia? Brittle bottles, easily fractured, and slow healing.
What is a classical presentation of ostegenesis imperfecta? Blue sclera, small misshapen teeth, abnormal ear ossicles leading to hearing defects.
Osteomalacia falls in what category of bone disease? Metabolic disease
What is osteomalacia? Soft bones due to poor mineralization.
What is cause of osteomalacia? Softening of bones caused by defective mineralization secondary to a vit D deficiency.
What do you call osteomalacia in kids? Rickets
What is the main regulator of conversion of 25-hydroxyvitamin D to 1,25-hydroxyvitamin D? Where does it take place? PTH; Kidney
Why is vitamin D important? Without vitamin D, only 10-15% of dietary calcium and 60% of phosphorous are absorbed.
What is the role(3) of PTH? Calcium resorption in kidney tubules. Convert vit D, promotes reabsorption of Ca in GI.Promotes osteoclasts activity.
What role does PTH have on osteoblasts? Activates osteoblasts, upregulating RANKL transforming immature osteoclasts to mature osteoclasts.
What is osteopenia? Low bone density
Type I Osteoporosis
What is type I osteoporosis? Post-menopausal characterized by increased osteoclasts activity and RAPID bone loss.
What is the cause of type II osteoporosis? Decreased estrogen due to menopause in women ~50yrs.
What percentage of bone loss is seen in post-menopausal osteoporosis? 5-10% trabeculae, 2% cortical per yr.
Where in the skeleton is bone loss/fractures experienced more? Why? Vertebrae, femur; Because more trabeculae bone.
What is the role of estrogen in osteclasts? Control the level of osteoclasts
How does estrogen regulate(2) osteoclasts? 1) Upregulates Fas Ligand >> increases osteoclasts apoptosis 2) Decreases sensitivity of RANKL on osteoclasts
How does a deficiency in estrogen cause osteoporosis? Increased remdoling by osteoclasts, decreases osteoblasts
What are the roles of cytokines TNF and IL-7 in osteoporosis? decrease osteoblasts activity and anti-apoptotic effects in osteoclasts prolonging life and acceleration resorption.
Type II Osteoporosis
What is Type II osteoporosis? Senile characterized by decreased osteoblasts activity. Slower bone loss.
What percentage of bone is loss in type II osteoporosis? 6 - 8% trabeculae 2 - 4% cortical bone in a decade
Name two drugs and their MOA that are used to prevent the accelerated bone loss. 1) biphosphonates (fosamax) - binds to hydroxyapatite cyrstals in the matrix slowing the removal by osteoclasts 2) Denosumab - humanized monoclonal antibody that binks RANKL inhibiting osteoclasts maturation
Why can an intermittent recombinant PTH 1-34(teriparatide) be used to treat new bone formation? Intermittent PTH results in activation of osteoblasts. The pharmokinetics of PTH depends on the time PTH remains above baseline.Continuous PTH results in bone loss.
Explain how Cushing's or prolonged exogenous steroid use accelerates bone loss? Compromise osteoblastic activity and decrease Ca2+ absorption in the gut. Decrease in Ca2+ results in increase PTH and activates osteoclasts.
Immobilization results in how much bone loss? 5% of skeleton per month.
Name two populations at risk of immobilzation bone loss astronauts and orthopedic procedure patients
What disease is associated with periarticular osteoporosis? Rheumatoid arthritis
Explain why RA leads(2) to periarticular osteoporosis. 1) Release of inflammatory cytokines IL-1 and TNF-alpha leads to destruction of epiphyseal bone. 2) Activated synovial lymphocytes release RANKL promoting osteoclasts activity.
Paget Disease of Bone
What is Paget Disease? Disease in which the BMU is uncoupled resulting in alternating dominant regions of OC or OB.
What is the classic pathognomonic histiologic of Paget Disease? Mosaic pattern of bone.
What is the progression of Paget Disease? Initially there is profound osteoclastic activity producing lytic lesion. Next, there is profound osteoblastic activity that result in sclerotic, deformed bones.
T/F In Paget Disease, bone mass decreases over time resulting in bone that is structurally abnormal and weak. False, bone mass increases over time due to profound OB activity. However, bone is like "chalk" and breaks.
When does Paget Disease begin? Mid adulthood and increases with age.
Describe the presentation of Paget Disease? Usually asymptomatic; Pain caused by microfractures is the most common presenting sign; Weight bearing results in anterior bowing of legs and distortion of femoral heads leading to secondary DJD; Overgrowth of vertebrae can compress spinal nerves.
What type of cancer(2) can Paget Disease develop? Osteosarcoma and chondrosarcoma
Degenerative Joint Disease
What is another name for DJD? Osteoarthritis
T/F DJD is the leading cause of permanent incapacity in age >50 yrs. False, second. Cardivascular is the leading cause.
T/F OA is the most common disease of the joint. True
T/F Men are affected by DJD more than women. False
Where does DJD appear first? In the distal interphalangeal joint(DIP) of the first finger and spreads gradually to involve other digits.
Where in the skeleton does DJD typically present? DIP, knees, hips, and verterbrae.
What is the name of the distorted DIP joints by prominent osteophytes? Heberden nodes
DJD is multifactorial, name 2 risk factors. Obesity leading to increase stress on weight bearing joints; Previous injury or developmental abnormality to joint.
What are the two main constituents of extracellular cartiaginous matrix? Type II collagen and aggrecan
What causes to DJD? Wear and tear of articular cartilage from uncontrolled loss of the EXTRACELLULAR CARTILAGINUOS MATRIX leading to death of chondrocytes.
Define fibrillation in terms of DJD. Articular surface that is shaggy due to death of chondrocytes.
Define eburnated bone. Hard, shiny articular surface of sclerotic bone.
What are osteophyes? Bone petrusions along the joint margin.
List 4 features of OA. Asymmetrical; Few joints severely affected; Decreased mobility in finger, spine, and affected joints; ankylosis typically not seen
Describe how RA presents different compared to DJD Inflammatory; Symmetrical; PIP; Fever and malaise is present; ankylosis
What is the rheumatoid factor present in 50% of RA pts? An IgM or IgA autoantibody against IgG that contribute to the inflammatory process.
Where else in the body does the inflammation of RA present? Heart and lungs and skin nodules
What are synovium and synoviocytes? Where are they found? Synovium-provides nutrients to cartilage and produces lubricants. Synoviocytes-are macrophage and fibroblasts that line beneath the synovium. Capsule surrounding joints.
In RA, what happens to the synoviocytes? They become hyperplastic and the synovium becomes infiltrated by CD4 T cells; B-cells; macrophages, and plasma cells.
What is a pannus? A sheet formed by aggressive and invasive synoviocytes that covers the articular cartilage.
Name two inflammatory mediators released from the reactive synovium that leads to breakdown of cartilage matrix. IL-1 and TNF-alpha
What causes the destruction of subarticular bone? RANKL is released from activated lymphocytes in synovial membranes and stimulates the development of osteoclasts.
What is subluxation? Dislocation or absence of a joint.
What is the most severe complication of RA? ankylosis
How can RA be treated? Antibodies against IL-1 and TNF-alpha
Describe 4 features of RA Inflammatory; Symmetrical; Affects small joints; Ankylosis
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