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PTH and vitamin D > Book 5(Sheet1) > Flashcards

Book 5(Sheet1) Flashcards

1
Q

where is PTH produced

A

parathyroid gland

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2
Q

where are the parathyroid glands

A

behind the thyroid gland

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3
Q

what are supernary parathyroid glands

A

having more than the normal 4 glands; can be up to 8; in 2-5% of the population

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4
Q

what cells produce PTH

A

chief cells

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5
Q

how is PTH produced (general steps)

A

produced as a 115 AA pre-pro-peptide; 25 AA signal peptide is cleaved to generate a pro-hormone

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6
Q

which amino acids are necessary for PTH function

A

the N terminal 1-34 residues

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7
Q

what is CasR

A

calcium sensing receptor located on chief cells

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8
Q

what happens when Ca binds to CasR

A

activates both Gi and Gq pathways; Gi pathway inhibits adenylyl cyclase, reduced cAMP production, inhibits PTH secretion; Gq pathway acts on PLC which produces DAG and IP3, DAG produces PKC and IP3 which stimulates Ca release, PKC inhibits PTH secretion

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9
Q

how is PTH released from chief cells

A

when Ca levels are low, the CasR becomes unbound which relieves the inhibition of PTH release

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10
Q

how is PTH metabolized

A

in kidney and liver, NH2 and C terminal fragments are generated; inactivated C terminal fragment is removed by glomerular filtration; N terminal 1-34 is bioactive

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11
Q

what happens to PTH metabolism in renal insufficiency

A

C terminal fragment is elevated in the blood

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12
Q

what is glial cell missing 2 (GCM2)

A

transcription factor originally identified in drosophila specific for the parathyroid gland

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13
Q

what happens in GCM2 KO mice

A

no parathyroid gland present

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14
Q

what happens to control mice Ca levels following their birth

A

Ca levels are reduced then increase back to normal once they start drinking their mother’s milk; normal is ~10 mg/dL

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15
Q

what happens to control mice phosphate levels following their birth

A

start around 12 mg/dL then drop to ~8 mg/dL

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16
Q

what happens to GMC2 mutated mice Ca levels following their birth

A

start with lower levels of Ca than normal, then further drop after birth; some recover to low levels and some continue to drop and die; there may be a secondary source of PTH that prevents total drop in some mice

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17
Q

what happens to GMC2 mutated mice phosphate levels following their birth

A

higher than normal

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18
Q

main effects of PTH on Ca and phosphate

A

PTH increases Ca levels and decreases phosphate levels

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19
Q

bone phenotype of Gcm2-/- mice

A

has almost double the mineralized bone as the control because there is impaired bone resorption

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20
Q

main roles of PTH

A

promotes bone resorption to increase Ca levels in blood, acts on kidney to promote reabsorption of Ca, promotes final hydroxylation of vitamin D which promotes absorption of Ca in the small intestine

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21
Q

describe the development of osteoblasts

A

embryonic stem cells become mesenchymal stem cells which become osteoblasts

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22
Q

describe the development of osteoclasts

A

embryonic stem cells become hematopoietic stem cells which become osteoclasts

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23
Q

role of osteoblasts

A

secrete calcium matrix which becomes mineralized to make bone

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24
Q

role of osteoclasts

A

involved in bone resorption

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25
Q

what is bone remodeling

A

bone resorption and bone formation happening together

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26
Q

what is bone modeling

A

either bone resorption or bone formation happen de novo without involving each other; typically during early stages of development

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27
Q

role of PTH in bone remodeling

A

PTH released when Ca levels are low; PTH binds to its receptor on osteoblasts (GPCR), triggers gene expression of RANKL, RANKL is released by osteoblasts and binds to its receptor RANK on osteoclasts which promotes maturation/differentiation of osteoclasts, osteoclasts secrete acid/proteases to degrade bone matrix and release Ca into bloodstream

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28
Q

what is teriparatide

A

recombinant PTH

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29
Q

what happens when PTH is given intermittently

A

improvement of bone mass which seems counterintuitive

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30
Q

why does intermittent PTH increase bone mass

A

PTH acts on T cells which promotes formation of Wnt10 from the T cells, Wnt10 promotes commitment of embryonic cells to osteoblast lineage, promotes proliferation and differentiation of osteoblasts, inhibits apoptosis of osteoblasts; since it is given intermittently, its short half life will give it enough time to act on T cells but before it can act directly on bone it is degraded

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31
Q

longer presence of PTH promotes ____, shorter presence promotes ____

A

bone resorption, bone formation

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32
Q

teriparatide works best when given at what time

A

in the morning, since these pathways are also regulated by circadian rhythm

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33
Q

what is PTHrP

A

The PTH- related peptide that acts on the same receptor as PTH but is more specialized for skeletal development

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34
Q

where is PTHrP most similar to PTH

A

have 8 identical residues in its first 13 residues

35
Q

PTHrP exists in ____ forms

A

3

36
Q

which cancers secrete PTHrP

A

squamous cell carcinoma of the lung and renal carcinoma

37
Q

describe the process of endochondral bone formation

A

start with a clump of mesenchymal cells that make the shape of the future bone, cells become chondrocytes and outer layer differentiates into osteoblasts; the core cells become large and form 4 zones of chondrocytes; the least advanced are at the ends and most advances are in the core; the cycle of chondrocyte growth and division causes the cartilage to increase in length; hypertrophic chondrocytes release collagen that is mineralized; at the same time blood vessels invade deep inside the core bringing in osteoclasts which produce acid to degrade mineralized collagen; osteoblasts then migrate or get differentiated from chondrocytes to secrete collagen that is mineralized into bone; this continuous as bones grow

38
Q

what type of collagen is secreted by chondrocytes

A

type 2 and 10

39
Q

what type of collagen is secreted by osteoblasts

A

type 1

40
Q

role of PTHrP in endochondral bone formation

A

resting chondrocytes make PTHrP, PTHrP inhibits IHH which is produced by pre hypertrophic cells; IHH promotes proliferation/differentiation of cells

41
Q

what are the 4 zones of chondrocytes starting from the inner layer and moving out

A

hypertrophic, prehypertrophic, proliferating, resting

42
Q

what happens to a mouse that is Pthrp-/-

A

everything happens too quickly, all the chondrocytes proliferate/differentiate and die too rapidly

43
Q

what causes primary hyperparathyroidism

A

hyper function of the parathyroid glands due to adenoma, hyperplasia, or carcinoma of the parathyroid glands

44
Q

results of primary hyperparathyroidism

A

loss of Ca homeostasis due to excessive PTH secretion, hypercalcemia

45
Q

less common cause of primary hyperparathyroidism

A

type 1 or 2a multiple endocrine neoplasia (MEN)

46
Q

what causes secondary hyperparathyroidism

A

excessive secretion of PTH by the PT glands in response to hypocalcemia and/or hyperphosphatemia, usually due to renal failure; other causes would be vitamin D deficiency, malnutrition

47
Q

results of secondary hyperparathyroidism

A

bone disease called renal osteodystrophy, phosphaturia, osteoporosis

48
Q

who is susceptible to secondary hyperparathyroidism

A

pregnant women since they have a greater demand on vitamin D

49
Q

what causes tertiary hyperparathyroidism

A

prolonged secondary hyperparathyroidism leading to hyperplasia of the parathyroid glands and loss of response to serum calcium levels

50
Q

which patients are more likely to develop tertiary hyperparathyroidism

A

patients with chronic renal failure

51
Q

what causes non PTH mediated hypercalcemia

A

commonly the result of multiple myeloma, breast cancer, or lung cancer and is caused by increased osteoclastic activity within the bone

52
Q

example of non PTH mediated hypercalcemia

A

in inflammatory granulomatous disease, extra-renal 1alpha(OH)ase is produced by macrophages in granuloma which increases the production of vitamin D, this increases Ca absorption from gut, increased Ca and vitamin D inhibit PTH production; causes hypercalciuria

53
Q

characteristics of hypoparathyroidism

A

reduced PTH and vitamin D, most symptoms caused by abnormal Ca and PO4

54
Q

types of hypoparathyroidism

A

PTH deficient, PTH ineffective, PTH resistant

55
Q

what causes PTH deficiency

A

removal of PT gland (post-operative), idiopathic atrophy of the PT gland, reduced or absent PTH synthesis due to mutation

56
Q

what causes PTH to be ineffective

A

rare condition with biologically inactive PTH production

57
Q

what is type 1a PTH resistance

A

Albright’s hereditary osteodystrophy

58
Q

what causes type 1a PTH resistance

A

Gs mutation: deficient response to all GPCRs coupled to AC

59
Q

side effects of type 1a PTH resistance

A

hypothyroidism, gonadal dysfunction, short stature, short fingers and toes

60
Q

what causes type 1b PTH resistance

A

some sort of PTH receptor defect

61
Q

what causes type 1c PTH resistance

A

defect downstream to G protein, so could be in the catalytic subunit of AC

62
Q

what causes type 2 PTH resistance

A

defective cAMP activation pathway; could be in PKA, PKA substrate, etc.

63
Q

what is vitamin D

A

fat soluble hormone essential for Ca and Pi metabolism that can travel through cell membranes

64
Q

what is the normal serum level of vitamin D

A

20-50 pg/mL

65
Q

loss of vitamin D causes….

A

hypophosphatemia and hypocalcemia

66
Q

effects of vitamin D

A

acts on PT gland to decrease PTH synthesis and release, acts on bone to help mineralization of newly formed bone matrix, acts on intestine to increase absorption of Ca and Pi, acts on immune system to induce differentiation of immune cells, acts on RBCs to improve hematopoiesis, acts on cancer cells to inhibit clonal proliferation

67
Q

first step of vitamin D production

A

7-dehydrocholesterol converted to pre-D3 by sunlight in the skin

68
Q

second step of vitamin D production

A

D3 converted to 25(OH)D3 by 25 hydroxylase in the liver

69
Q

third step of vitamin D production

A

25(OH)D3 converted to 1,25(OH)2D3 by 1alpha hydroxylase in the kidney

70
Q

how is vitamin D production regulated

A

both enzymes receive feedback inhibition from their products and PTH acts on 1alpha hydroxylase to increase production of vitamin D

71
Q

how is an inactive form of vitamin D produced

A

25(OH)D3 can be converted to 24,25(OH)2D3 by 24 hydroxylase

72
Q

mode of action of vitamin D

A

vitamin D is bound to DBP in the blood and transported to cell, vitamin D enters the cell and goes to the nucleus where it binds to VDR which forms a dimer with RXR, this dimer binds to gene promoters to increase production of calcium transporter ionophore, Ca binding protein, and Ca ATPase to release Ca into circulation

73
Q

4 important domains on the vitamin D receptor

A

transcription activating domain, ligand binding domain, DNA binding domain, COOH end where inhibitory proteins such as heat shock proteins bind

74
Q

how do hormone response elements confer specificity to which nuclear receptor can bind

A

orientation, distance between two sequences and unrelated external recognition sequences

75
Q

most commonly found sequence recognized by vitamin D

A

direct repeat

76
Q

what is vitamin D dependent rickets

A

hypertrophic chondrocytes do not become osteoblastic or go through apoptosis due to lack of vitamin D which leads to widened growth plate

77
Q

what causes VDDR1A

A

enzymatic defect in synthesis of the active form of vitamin D caused by a mutation in the D3-1-alpha hydroxylase gene

78
Q

results of VDDR1A

A

inability to walk, bone deformities, seizures, hypocalcemia, decreased serum 1,25(OH)2D3, hyperparathyroidism

79
Q

what causes VDDR1B

A

mutation in the gene encoding vitamin D 25-hydroxylase

80
Q

results of VDDR1B

A

leg bone abnormalities, low serum Ca, low serum Pi, elevated serum alkaline phosphatase, low 25(OH)D3

81
Q

treatment of VDDR1A

A

dosage of active vitamin D (calcitriol/1,25OHD3)

82
Q

treatment of VDDR1B

A

high dosage of 25(OH)D3

83
Q

cause of VDDR2A

A

caused by end organ unresponsiveness of active vitamin D due to mutation in the gene encoding the vitamin D receptor

84
Q

cause of VDDR2B

A

unusual form of end-organ unresponsiveness to active vitamin D due to an abnormal nuclear ribonucleoprotein that interferes with the function of VDR (vitamin D receptor)

PTH and vitamin D (2 decks)

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