Pathology (bone excluding tumor)

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Pathology (bone excluding tumor)
2013-09-14 14:07:48

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  1. What is the major determinant of peak BMD?
  2. What is the action of osteoprogenitors?
    Produce osteoblast via WNT/β-catenin signaling pathway
  3. What are the actions of osteoblasts?
    • 1. Synthesize, transport, and arrange the many proteins of matrix
    • 2. Initiate the process of mineralization.
    • 3.Have receptors that bind regulatory hormones (parathyroid hormone, vitamin D, leptin, and estrogen), cytokines, growth factors, and extracellular matrix proteins
    • 4. Express several factors that regulate the differentiation and function of osteoclasts
    • 5. If osteoblasts become surrounded by newly deposited organic matrix, they transform into osteocytes;
    • 6. Osteoblasts remaining on the bone surface may become flattened and quiescent bone lining cells.
  4. What are the actions of osteocytes?
    • 1. Communicate with each other and with cells on the bone surface via an intricate network of cytoplasmic processes that traverse tunnels in the matrix known as canaliculi.
    • 2. Help to control calcium and phosphate levels in the microenvironment
    • 3. Detect mechanical forces and translate them into biologic activity—a process called mechanotransduction
  5. What are the precursors of osteoclasts?
    same hematopoietic progenitor cells that also give rise to monocytes and macrophages
  6. What are action of osteoclasts?
    • 1. Bone resorption
    • 2. Mature multinucleated osteoclasts form from the fusion of circulating mononuclear precursors and have a limited life span (approximately 2 weeks). They bind to the bone surface via integrins, where they form an underlying resorption pit. The cell membrane overlying the resorption pit is thrown into numerous folds (the ruffled border), increasing its surface area, while the adjacent cell surface forms a tight seal with the bone that prevents leakage of digestion products.
    • 3. The osteoclast removes the mineral by generating an acidic environment utilizing a proton pump system and digests the organic component by releasing proteases.
  7. What cytokines and growth factors regulate human osteoclast differentiation and maturation?
    • M-CSF
    • IL-1
    • TNF
  8. What are the pathways associated with bone homeostasis?
    • (1) the transmembrane receptor RANK (receptor activator for NF-κB) on osteoclast precursors; (2) RANKL on osteoblasts and marrow stromal cells; and (3) osteoprotegrin (OPG), a secreted “decoy” receptor made by osteoblasts and several other types of cells that can bind RANKL and thus short-circuit its interaction with RANK. When stimulated by RANKL, RANK signaling activates the NF-κB, which is essential for the generation and survival of osteoclasts. 
    • B
    • M-CSF produced by osteoblasts and the M-CSF receptor, which is expressed by osteoclast progenitors. Activation of the M-CSF receptor stimulates a tyrosine kinase activity that is also crucial for the generation of osteoclasts

    • C
    • WNT proteins produced by marrow stromal cells bind to the LRP5 and LRP6 receptors on osteoblasts  and thereby trigger the activation of β-catenin and the production of OPG
  9. What are the pathways associated with bone homeostasis?
    • 1. WNT (stromal cell) to LRP5/6 on osteoblasts--> beta-catenin--> osteoprotegrin (bind RANKL--> inhibit its binding to RANK--> inhibit osteoclast differentiation)
    • 2. M-CSF by osteoblast bind to receptor on osteoclast progenitor--> differentiate osteoclast
    • 3. RANKL by osteoblast binds RANK on osteoclast precursor--> activate NF-kappa B --> osteoclast differentiation
  10. What two factors act in opposite direction to change bone resoprtion?
    • Osteoprotegrin (increased via Wnt/beta catenin pathway)--> decrease bone resorption
    • RANKL (increases NF-kappaB)--> increase bone resorption
  11. How it occurs that as bone is broken down to its elemental units, substances are released into the microenvironment that initiate its renewal?
    As osteoclasts disassemble matrix proteins deposited by osteoblasts, growth factors, cytokines, and enzymes (such as collagenase) bound to the matrix are liberated and activated, including some that stimulate osteoblasts.
  12. What is the most important protein of bone matrix?
    Type I collagen
  13. What protein in unique to bone matrix?
  14. Osteoclacin is the marker for which bone cell?
  15. What is the difference between woven bone and lamellar bone?
    • Osteoblasts deposit collagen either in a random weave known as woven bone or in an orderly layered manner designated lamellar bone.
    • Normally, woven bone is seen in sites of rapid bone formation such as the fetal skeleton and the base of growth plates. It resists forces equally from all directions.
    • The presence of woven bone in the adult is always abnormal; however, it is not diagnostic of a particular disease.
    • Lamellar bone, which gradually replaces woven bone during growth, is deposited much more slowly and is stronger than woven bone.
  16. What is the main mechanism of bone formation?
  17. How is enchondral bone ossification begin?
    Around the eighth week of gestation the process of enchondral ossification begins, and the cartilage is removed by osteoclast-type cells forming the medullary canal.
  18. How are primary and secondary centers of ossification formed?
    The periosteum in the midshaft generates osteoblasts that deposit the beginnings of the cortex; this region is known as the primary center of ossification. A similar sequence of events occurs in the epiphysis, resulting in the removal of cartilage and deposition of bone in a centrifugal fashion (secondary center of ossification)
  19. What is the growth plate?
    a plate of the cartilage anlage becomes entrapped between the expanding centers of ossification forming the physis or growth plate
  20. What is responsible for bone longitudinal growth?
    • The chondrocytes within the growth plate are responsible for longitudinal growth as they undergo a series of changes, including proliferation, growth, maturation, and apoptosis
    • Controlled by a number of signaling pathways, including those involving FGFR and BMP, hedgehog protein, and PTH-related protein. In the region of apoptosis the matrix mineralizes and is resorbed by osteoclasts
    • Remnant struts persist and act as scaffolding for the deposition of bone on their surfaces. These structures are known as primary spongiosa and are the first bony trabeculae.
    • A similar process occurs at the base of articular cartilage, and by this mechanism bones increase in length, and articular surfaces increase in diameter. 
  21. How is intramembranous bone formation?
    cranium and lateral portions of the clavicles, are formed by osteoblasts directly from a fibrous layer of tissue that is derived from mesenchyme. Because bone tissue is made only by osteoblasts, the enlargement of bones is achieved by the deposition of new bone on a preexisting surface
  22. What are the zones of bone in enchondral calcification?
    Active growth plate with ongoing enchondral ossification. 1, Reserve zone. 2, Zone of proliferation. 3, Zone of hypertrophy. 4, Zone of mineralization. 5, Primary spongiosa.

  23. What are the genes responsible for bone development?
    Homeobox genes
  24. What are the three kinds of abnormal development of bone?
    • 1)Localized problems in the migration of the mesenchymal cells and the formation of the condensations are known as dysostoses (mutations transcription factors e.g., homeobox genes)--> polysyndactyly, Waardenberg syndrome
    • 2) mutations in the regulators of skeletal organogenesis, such as signaling molecules (e.g., growth factors and their receptors--> achondroplasia) and 3) matrix components (e.g., types 1 collagen--> OI) affect cartilage and bone tissues globally; these disorders are known as dysplasias.
  25. What are the features of achondroplasia?
    • MC disease of the growth plate and is a major cause of dwarfism.
    • Caused by a gain-of-function mutation in the FGFR3.
    • Normally, FGFmediated activation of FGFR3 inhibits cartilage proliferation; in achondroplasia, the mutations cause constitutive activation of FGFR3 and thereby suppress growth.
    • AD, 80% of cases stem from new mutations, almost all of which occur in the paternal allele. 
    • Shortened proximal extremities, a trunk of relative normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose.
    • Not associated with changes in longevity, intelligence, or reproductive status
  26. What is the mc disease of growth plate?
  27. What is the mc lethal form of dwarfism?
    Thanatophoric dwarfism
  28. What are the features of thanatotrophic dwarfism?
    • MC lethal form of dwarfism
    • Caused by gain-of-function mutations in FGFR3
    • Micromelic shortening of the limbs, frontal bossing, relative macrocephaly, a small chest cavity, and a bell-shaped abdomen. The underdeveloped thoracic cavity leads to respiratory insufficiency
  29. What disorders are produced by loss and gain of function mutation in LPR5?
    Decreased bone mass/ increased bone mass ( decreased and increased Wnt/beta catenin pathway to produce OPG)
  30. What is the genetic features of OI?
    Collagen type I, most AD, except type II (lethal form) which is mostly AR
  31. What is the mc inherited disorder of connective tissue?
  32. Which tissues are affected by OI?
    joints, eyes, ears, skin, and teeth and bone
  33. How mutations in OI affect course of the disease?
    • Mutations resulting in decreased synthesis of qualitatively normal collagen are associated with mild skeletal abnormalities.
    • More severe or lethal phenotypes have abnormal polypeptide chains that cannot be arranged in the triple helix
  34. What are the types of OI?
    • I--> normal stature, blue sclera, reduced Fx after puberty, normal survival
    • II--> perinatal death
    • III--> progressively deforming, blue sclera
    • IV--> normal sclera, mild skeletal abnormality
  35. What are the symptoms of OI?
    • 1)Blue sclerae making the sclera translucent and allowing partial visualization of the underlying choroid
    • 2)Both SNHL and CHL
    • 3)Small, misshapen, and blue-yellow teeth secondary to a deficiency in dentin
    • 4)The basic abnormality in all forms of osteogenesis imperfecta is too little bone, thus constituting a type of osteoporosis with marked cortical thinning and attenuation of trabeculae.
  36. What is the major defect in MPS?
    Deficiencies in the acid hydrolases that degrade dermatan sulfate, heparan sulfate, and keratan sulfate
  37. What is the most important cell and tissue affected by MPS?
    Chondrocytes/ hyaline cartilage, including the cartilage anlage, growth plates, costal cartilages, and articular surfaces
  38. What is the pathophysiology of osteopetrosis?
    • Reduced bone resorption and diffuse symmetric skeletal sclerosis due to impaired formation or function of osteoclasts
    • Most of the mutations underlying osteopetrosis interfere with the process of acidification of the osteoclast resorption pit, which is required for the dissolution of the calcium hydroxyapatite within the matrix
  39. What are the histological features of osteopetrosis?
    • Lack of medullary canal
    • The ends of long bones are bulbous (Erlenmeyer flask deformity)
    • The neural foramina are small and compress exiting nerves.
    • The primary spongiosa, which is normally removed during growth, persists and fills the medullary cavity, leaving no room for the hematopoietic marrow and preventing the formation of mature trabeculae Deposited bone is not remodeled and tends to be woven in architecture.
    • The number of osteoclasts is variable
  40. How is osteopetrosis treated?
  41. What are the clinical features of osteopetrosis?
    • Severe infantile malignant osteopetrosis is AR. Fracture, anemia, and hydrocephaly, cranial nerve defects (optic atrophy, deafness, and facial paralysis) and repeated—often fatal—infections because of inadequacies of the marrow produced in extramedullary sites, which also causes prominent hepatosplenomegaly.
    • The mild autosomal dominant benign form may not be detected until adolescence or adulthood, when it is discovered on x-rays performed because of repeated fractures, mild anemia, mild CN deficit.
  42. What is mcc of osteomyelitis?
    Staph.aureus (has specific binding receptors for ECM of bone)
  43. What are the major causes of osteomyelitis?
    • 1. Staph.aureus (mc)
    • 2. Ecoli, klebsiella, Pseudomona in IDU or GU infection
    • 3. Pseudomona in puncture wound
    • 4. GBS, HI in infants
    • 5. Salmonella (nontyphi) in SCD
    • 6. Mixed infection in surgery or open fracture
  44. What is the mc origin of osteomyelitis in children and adults?
    • Children--> hematogenous/the long bones. trivial injuries to the mucosa or minor infections of the skin.
    • Adults-->open fractures, surgical procedures, and diabetic infections of the feet.
  45. What is the location of osteomyelitis?
    • In the neonate the metaphyseal vessels penetrate the growth plate--> metaphysis, epiphysis.
    • In children-->metaphysis
    • After growth plate closure, the metaphyseal vessels reunite with their epiphyseal -->seed the epiphyses and subchondral regions in the adult.
  46. What are the specific morphological features of osteomyelitis in each age group?
    • In children the periosteum is loosely attached to the cortex;subperiosteal abscesses 
    • In infants, but uncommonly in adults, epiphyseal infection spreads through the articular surface or along capsular and tendoligamentous insertions into a joint, producing septic or suppurative arthritis
  47. What are the histological hallmarks of osteomyelitis?
    • Bone necrosis--> sequestrum.
    • Rupture of the periosteum leads to a soft-tissue abscess and the eventual formation of a draining sinus.
    • After the first week chronic inflammatory cells become more numerous and their release of cytokines stimulates osteoclastic bone resorption, ingrowth of fibrous tissue, and the deposition of reactive bone in the periphery. When the newly deposited bone forms a sleeve of living tissue around the segment of devitalized infected bone, it is known as an involucrum 
  48. What are the two morphological variants of osteomyelitis?
    Brodie abscess is a small intraosseous abscess that frequently involves the cortex and is walled off by reactive bone; sclerosing osteomyelitis of Garré typically develops in the jaw and is associated with extensive new bone formation that obscures much of the underlying osseous structure.
  49. What is the radiological hallmark of osteomyelitis?
    lytic focus of bone destruction surrounded by a zone of sclerosis
  50. What are the complications of chronic osteomyelitis?
    Acute flare, pathologic fracture, secondary amyloidosis, endocarditis, sepsis, development of squamous cell carcinoma in the sinus tract, and rarely sarcoma in the infected bone
  51. What is the mc primary origin of TB osteomyelitis?
    blood borne and originate from a focus of active visceral disease during the initial stages of primary infection.
  52. What are the mc involving bones in TB osteomyelitis?
    spine (40% of cases, especially the thoracic and lumbar vertebrae) >knees and hips
  53. What is the hallmark of TB osteomyelitis?
    the infection breaks through intervertebral discs to involve multiple vertebrae and extends into the soft tissues forming abscesses.
  54. What are the complications of TB vertebral osteomyelitis?
    • Permanent compression fractures that produce severe scoliotic or kyphotic deformities and neurologic deficits secondary to spinal cord and nerve compression.
    • Tuberculous arthritis
    • Sinus tract formation
    • Psoas abscess
    • Amyloidosis.
  55. What are the hallmarks of bone involvement in syphilis?
    • Involvement of active enchondral ossification (osteochondritis) and in the periosteum (periostitis) in congenital.
    • The syphilitic saber shin is produced by massive reactive periosteal bone deposition on the medial and anterior surfaces of the tibia.
  56. What are the major causes of osteoporosis?
    • PRIMARY: Postmenopausal,  Senile,   Idiopathic
    • Endocrine Disorders: Hyperparathyroidism, Hyperthyroidism, Hypogonadism, DM1, Addison disease
    • Neoplasia: MM, Carcinomatosis Gastrointestinal:Malnutrition, Malabsorption, Hepatic insufficiency, Vitamin C, D deficiencies
    • Drugs: Heparin, Chemotherapy,   Corticosteroids,   Anticovulsants,   Alcohol, GNRH agonist, Aromatase inhibitor
    • Miscellaneous: OI,Immobilization
  57. What are the mcc of osteoporosis?
    • Senile (low turn-over)
    • Postmenopausal osteoporosis (High turnover)
  58. What are the determinants of peak bone mass?
    • Genetic
    • Physical activity, muscle strength, diet, and hormonal state
  59. What is the difference in age-related bone between male and female?
    It is equal
  60. What are the most important genetic determinants of osteoporosis?
    • RANKL, OPG, and RANK
    • Estrogen receptor and MHC also play a role
  61. What are the three factors associated with senile (low turn over) osteoporosis?
    • Age
    • Body Calcium status
    • Physical activity
  62. What are the major determinant of postmenopausal (high turn over) osteoporosis?
  63. How does age affect bone status?
    • Osteoblasts from elderly individuals have reduced proliferative and biosynthetic potential
    • Proteins bound to the extracellular matrix (such as growth factors, which are both mitogenic to osteoprogenitor cells and stimulate osteoblastic synthetic activity) lose their biologic punch over time.
    • The net result is a diminished capacity to make bone. (senile osteoporosis or low-turnover variant)
  64. What is the importance of physical activity in bone health?
    • Mechanical forces stimulate normal bone remodeling.
    • Load magnitude influences bone density more than the number of load cycles. Because muscle contraction is the dominant source of skeletal loading, resistance exercises such as weight training are more effective stimuli for increasing bone mass than repetitive endurance activities such as jogging.
  65. What is the difference in calcium intake between adolescence boys and girls?
    Girls (but not boys) have insufficient calcium intake in the diet.
  66. What kind of bone is more lost as a result of estrogen deficiency?
    cancellous bone
  67. How does estrogen protect bone against loss?
    • The effects of estrogen on bone mass are mediated by cytokines.
    • Decreased estrogen levels appear to result in increased secretion of inflammatory cytokines by blood monocytes and bone marrow cells.
    • These cytokines stimulate osteoclast recruitment and activity by increasing the levels of RANKL while diminishing the expression of OPG.
    • Compensatory osteoblastic activity occurs, but it does not keep pace, leading to what is classified as a high-turnover form of osteoporosis.
  68. What is the mediator of estrogen deficiency on bone loss?
  69. What is the difference in pathophysiology of postmenopausal and senile osteoporosis ?
  70. What are the morphological features of senile and PMP osteoporosis?
    • The entire skeleton is affected in both.
    • 1. In postmenopausal osteoporosis the increase in osteoclast activity affects mainly bones or portions of bones that have increased surface area, such as the cancellous compartment of vertebral bodies.
    • The trabecular plates become perforated, thinned, and lose their interconnections, leading to progressive microfractures and eventual vertebral collapse.
    • 2. In senile osteoporosis the cortex is thinned by subperiosteal and endosteal resorption, and the haversian systems are widened. In severe cases the haversian systems are so enlarged that the cortex mimics cancellous bone. The bone that remains is of normal composition.
  71. What is the mechanism of action of bisphosphonate?
    inhibition of osteoclasts
  72. What are the two types of osteonecrosis?
    • Subchondral
    • Medullary
  73. Which artery is responsible for supplying the head of femor?
    Medial circumflex femoral
  74. What is the most sensitive test for Dx of osteonecrosis?
  75. What are the radiological signs of osteonecrosis?
    • MRI--> margin of low signal+ inner border of high signal
    • CT-->central necrosis +area of collapse
    • Scan--> early:reduced uptake late: increased uptake
    • X-ray--> early: osteopenia, late: collapse (increased density)
  76. What are the most important causes of osteonecrosis?
    Trauma, Corticosteroid , Infection, Dysbarism (e.g., the “bends”), Gaucher disease, Sickle cell, Alcohol abuse
  77. What are the morphological features of medullary infarct?
    Medullary infarcts are geographic and involve the cancellous bone and marrow. The cortex is usually not affected because of its collateral blood flow. 
  78. What are the morphological features of subchondral infarcts?
    In subchondral infarcts, a triangular or wedge-shaped segment of tissue that has the subchondral bone plate as its base undergoes necrosis. The overlying articular cartilage remains viable because it receives nutrition from the synovial fluid. 
  79. What happens to dead bone after osteonecrosis?
    • The dead bone, recognized by its empty lacunae, is surrounded by necrotic adipocytes that frequently rupture, releasing their fatty acids, which bind calcium and form insoluble calcium soaps that may persist for life.
    • In the healing response, osteoclasts resorb the necrotic trabeculae; however, those that remain act as scaffolding for the deposition of new bone in a process known as creeping substitution.
    • In subchondral infarcts the pace of this substitution is too slow to be effective, so there is eventual collapse of the necrotic cancellous bone and distortion, fracture, and even sloughing of the articular cartilage.
  80. What are the symptoms of osteonecrosis?
    • Subchondral infarcts cause chronic pain that is initially associated only with activity but then becomes progressively more constant as secondary changes supervene--> osteoarthritis
    • Medullary infarcts are clinically silent except for large ones occurring in Gaucher disease, dysbarism, and sickle cell anemia. Medullary infarcts usually remain stable over time.
  81. What are the features of osteochondritis dissecans?
    • Caused by trauma
    • Portion of cartilage and underlying subchondral bone separates
    • Mc in lateral surface of medial condyle
    • Lateral knee pain +intermittent locking and swelling
    • Tenderness over condyle in knee flexed
  82. What are the features of Osgood Schlatter disease?
    • Active boys
    • Painful swelling of tibial tuberosity (osteochondrosis)
    • Aggravated by squatting, walking upstairs, extending knee (quadriceps)
  83. What are the stages of paget disease?
    • (1) an initial osteolytic stage
    • (2) a mixed osteoclastic-osteoblastic stage, which ends with a predominance of osteoblastic activity and evolves ultimately into
    • (3) a burnt-out quiescent osteosclerotic stage
  84. What are the epidemiological features of Paget disease?
    • After 70 years
    • MC in Europe (not Scandinavia) and US
  85. What is the mechanism of Paget disease?
    • 80% sporadic
    • 20% AD--> 50% SQSTM mutations enhance NF-κB activation by RANK signaling, leading to increased osteoclast activity
  86. What is the pathological hallmark of paget disease?
    mosaic pattern of lamellar bone
  87. What is the mc presentation of Paget disease?
  88. What is the mc symptom of Paget disease?
    Bone pain
  89. What is the mc bone involved in Paget disease?
    The axial skeleton or proximal femur
  90. Which bone involvement is unusual in Paget disease?
    ribs, fibula, and small bones of the hands and feet
  91. What are the symptoms of Paget disease
    • Pain caused by micro fracture or nerve compression
    • Enlargement of the craniofacial skeleton --> leontiasis ossea and a cranium so heavy to hold the head erect.
    • Invagination of the skull base (platybasia) and compression of the posterior fossa structures.
    • Anterior bowing of the femurs and tibiae and distorts the femoral heads, resulting in the development of severe secondary osteoarthritis. 
    • Chalkstick-type fractures in the long bones of the lower extremities.
    • Compression fractures --> kyphoses.
    • The hypervascularity of pagetic bone --> high output failure
  92. What are the tumors seen in Paget disease?
    • GCT
    • giant-cell reparative granuloma
    • extra-osseous masses of hematopoiesis
    • Osteosarcoma and fibrosarcoma (more common in polyostotic disease)
  93. What is the radiological features of Paget disease?
    • Pagetic bone is typically enlarged with thick, coarsened cortices and cancellous bone.
    • Active disease has a wedge-shaped lytic leading edge that may progress along the length of the bone at a rate of 1 cm per year
  94. What are treatment options for Paget disease?
    calcitonin and bisphosphonates
  95. What is the major source of VitD in human?
    Endogenous synthesis in the skin by photochemical conversion of a precursor, 7-dehydrocholesterol,via UVB radiation. ( cholecalciferol= vitamin D3)
  96. What is major determinant of vitamin D synthesis in the skin other than UVB ?
    Skin pigmentation (the darker--> the lower amount of Vitamin D that is produced)
  97. What are the main steps in Vitamin D synthesis?
    • 1.   Photochemical synthesis of vitamin D from 7-dehydrocholesterol in the skin and absorption of vitamin D from foods and supplements in the gut  
    • 2.   Binding of vitamin D from both of these sources to plasma α1-globulin (D-binding protein or DBP) and transport into the liver  
    • 3.   Conversion of vitamin D into 25-hydroxycholecalciferol (25-OH-D) in the liver, through the effect of 25-OHases ( CYPs)  
    • 4.   Conversion of 25-OH-D into 1,25-dihydroxyvitamin D, [1α, 25(OH)2D3] in the kidney, the most active form of vitamin D, through the activity of α1-hydroxylase
  98. How is production of Active vitamin D regulated?
    • (a) hypocalcemia stimulates secretion of PTH, which in turn augments the conversion of 25-OH-D into 1,25-dihydroxyvitamin D by activating 1α-hydroxylase; (b) hypophosphatemia directly activatesα1-
    • hydroxylase 
    • (c) through a feedback mechanism, increased levels of 1,25dihydroxyvitamin D down-regulate its own synthesis through inhibition of 1α-hydroxylase activity.
  99. What is the mechanism of action of vitamin D?
    • It binds to the high-affinity vitamin D receptor (VDR), which associates with the RXR. This heterodimeric complex binds to vitamin D response elements located in the promoter of vitamin D target genes. The receptors for 1,25-dihydroxyvitamin D are present in most cells of the body and transduce signals that regulate plasma levels of calcium and phosphorus, through action on the small intestine, bones, and kidneys.
    • Beyond its role on skeletal homeostasis, vitamin D also has immunomodulatory and antiproliferative effects. More recently it has been proposed that 1,25-dihydroxyvitamin D may also act through nongenomic mechanisms, which do not require the transcription of target genes. Nongenomic mechanisms may involve the binding of 1,25-dihydroxyvitamin D to a membrane vitamin D receptor, leading to the activation of protein kinase C and opening of calcium channels
  100. What are the effects of vitamin D?
    • Stimulation of intestinal calcium absorption in duodenum through binding with nuclear VDR and forming complex with RXR--> produce calcium transport channel (through TRPV6)
    • Stimulation of calcium reabsorption in the DCT (by another member of vanilloid receptor family --> TRPV5 (also regulated by PTH)
    • Interaction with PTH in the regulation of blood calcium. Vitamin D maintains calcium and phosphorus at supersaturated levels in the plasma. 1,25-dihydroxyvitamin D and PTH enhance the expression of RANKL (receptor activator of NF-κB ligand) on osteoblasts--> increased osteoclast activity
    • Mineralization of bone. Vitamin D contributes to the mineralization of osteoid matrix and epiphyseal cartilage in the formation of both flat and long bones in the skeleton. It stimulates osteoblasts to synthesize the calcium-binding protein osteocalcin, involved in the deposition of calcium during bone development.
  101. How are flat and long bones developed?
    • Flat bones develop by intramembranous bone formation, in which mesenchymal cells differentiate directly into osteoblasts, and synthesize the collagenous osteoid matrix on which calcium is deposited.
    • Long bones develop by endochondral ossification, through which growing cartilage at the epiphyseal plates is provisionally mineralized and then progressively resorbed and replaced by osteoid matrix that is mineralized to create bone
  102. What happens when hypocalcemia occurs in vitamin D deficiency?
    • PTH production is elevated, causing (1) activation of renal 1α-hydroxylase, increasing the amount of active vitamin D and calcium absorption; (2) increased resorption of calcium from bone by osteoclasts; (3) decreased renal calcium excretion; and (4) increased renal excretion of phosphate.
    • FGF 23, which is produced by bone, is one of a group of agents known as phosphatonins, which block the absorption of phosphate in the intestine, and phosphate reabsorption in the kidney, causing increased urinary excretion of phosphate.
    • Although a normal serum level of calcium may be restored, hypophosphatemia persists, impairing the mineralization of bone. Increased production of FGF 23 may be responsible for tumor-induced osteomalacia and some forms of hypophosphatemic rickets
  103. What are the main causes of Vitamin D deficiency?
    • Nutritional
    • Reduced Sunlight
    • Multiple pregnancies
    • Children born to multiparous mothers that frequently breastfed
  104. Which food can be used to treat vitamin D deficiency?
    Fish oil
  105. What is the basic derangement in both rickets and osteomalacia ?
    an excess of unmineralized matrix
  106. What is the sequence in rickets?
    • Overgrowth of epiphyseal cartilage due to inadequate provisional calcification and failure of the cartilage cells to mature and disintegrate  
    • Persistence of distorted, irregular masses of cartilage, which project into the marrow cavity  
    • Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants  
    • Disruption of the orderly replacement of cartilage by osteoid matrix, with enlargement and lateral expansion of the osteochondral junction
    • Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone resulting from microfractures and stresses on the inadequately mineralized, weak, poorly formed bone  
    • Deformation of the skeleton due to the loss of structural rigidity of the developing bones
  107. What are the symptoms of Rickets?
    • Rickets is most common during the first year of life.
    • During the nonambulatory stage of infancy, the head and chest sustain the greatest stresses. 
    • 1) The softened occipital bones may become flattened, and the parietal bones can be buckled inward by pressure; with the release of the pressure, elastic recoil snaps the bones back into their original positions (craniotabes).
    • 2) An excess of osteoid produces frontal bossing and a squared appearance to the head.
    • 3) Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing the “rachitic rosary.” 
    • 4) The weakened metaphyseal areas of the ribs are subject to the pull of the respiratory muscles and thus bend inward, creating anterior protrusion of the sternum (pigeon breast deformity).
    • 5) When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and tibia, causing lumbar lordosis and bowing of the legs
  108. What are the symptoms of osteomalacia?
    • 1) The excess of persistent osteoid that is characteristic of osteomalacia.
    • 2) The contours of the bone are not affected
    • 3) The bone is weak and vulnerable to gross fractures or microfractures, which are most likely to affect vertebral bodies and femoral necks.
  109. What is the histological feature of inadequate bone mineralization?
    the unmineralized osteoid can be visualized as a thickened layer of matrix (which stains pink in hematoxylin and eosin preparations) arranged about the more basophilic, normally mineralized trabeculae.
  110. Which tissues can produce 1,25 OH vitamin D?
    Macrophages, keratinocytes, and breast, prostate, and colon
  111. What is the importance of vitamin D production in macrophages?
    Within macrophages, synthesis of 1,25-dihydroxyvitamin D occurs through the activity of CYP27B located in the mitochondria. Pathogen-induced activation of Toll-like receptors in macrophages causes a transcription-induced increase in vitamin D receptor and CYP27B . The resultant production of 1,25-dihydroxyvitamin D then stimulates the synthesis of cathelicidin, an antimicrobial peptide from the defensin family, which is effective against infection by Mycobacterium tuberculosis.
  112. What is the main difference in the bones affected between HPTH and osteoporosis?
    • HPTH--> cortical
    • Osteoporosis--> cancellous
  113. What are the histological features of HPTH?
    • 1) Affects cortical bone (subperiosteal, osteonal, and endosteal surfaces) more severely than cancellous bone.
    • 2) Subperiosteal resorption produces thinned cortices and the loss of the lamina dura around the teeth.
    • 3) In cancellous bone, osteoclasts dissect centrally along the length of the trabeculae, creating the appearance of railroad tracks and producing what is known as dissecting osteitis  (osteopenia)
    • 4) Osteoblast activity is also increased in hyperparathyroidism.
    • 5) The marrow spaces around the affected surfaces are replaced by fibrovascular tissue
    • influx of macrophages and an ingrowth of reparative fibrous tissue, creating a mass of reactive tissue (brown tumor) --> brown due to hemosiderin and vascularity
    • 6) Increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors is the hallmark of severe hyperparathyroidism and is known as generalized osteitis fibrosa cystica
  114. What are the major consequences of bone diseases in CRF?
    (1) increased osteoclastic bone resorption mimicking osteitis fibrosa cystica, (2) delayed matrix mineralization (osteomalacia), (3) osteosclerosis, (4) growth retardation, and (5) osteoporosis
  115. What are the major bone diseases in CRF?
    • 1) high turn over--> OFC (increased osteoblastic and clastic activity. clastic>blastic) due to high PTH
    • 2) low turnover (adynamic bone disease due to low PTH)--> reduced clastic and blastic activity/ both reduced mineralization and osteoid formation
    • 3) low turn over (osteomalacia) due to aluminium toxicity, both reduced blastic and clastic activity, only reduced mineralization
  116. What is the cause of OFC in CRF?
    • Increased P (inhibit 1,25OH vitamin D further)  and reduced 1,25OH vitamin D (reduced Ca)--> increased PTH (also Parathyroid resistance to FGF23, vitamine D, Calcium, and Klotho)
    • Metabolic acidosis enhance demineralizaion
  117. What is the action of FGF23?
    • Produced by osteocytes
    • Stimulated by high 1,25 OH vitamin D and P
    • Reduce Phosphate absorption, 1 alpha hydroxylase and PTH
  118. What is the major bone disease in dialysis patients?
    Adynamic bone disease
  119. What are RF for adynamic bone disease?
    • Increased age
    • DM
    • Increased Ca (Ca containing phosphate binder), and Vit D intake
    • All cause suppressed PTH
  120. What is the major cause of osteomalacia in RF?
    • Aluminium
    • The sources of the aluminum include dialysis solutions and oral aluminum-containing phosphate binders.
    • Aluminum interferes with the deposition of calcium hydroxyapatite and hence results in osteomalacia.
    • Also cause of dialysis encephalopathy and microcytic anemia
  121. How can vitamin K deficiency result in bone disease ?
    Reduced gamma carboxylation of osteocalcin
  122. What is the major form of amyloidosis in hemodialysis patients?
    • β2-microglobulin
    • Involves bone and periarticular structures