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BMS 460 > Growth Hormone > Flashcards

Growth Hormone Flashcards

1
Q

what does GH stimulate?

A

IGF-1 (produced by hepatocytes)

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2
Q

what stimulates GH?

A

GHRH stimulates release of GH from acidophils (in anterior pituitary)

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3
Q

what inhibits the release of GH?

A
  • somatostatin
  • high blood glucose levels
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4
Q

what does IGF-1 stimulate?

A

growth of long bones by stimulating hypertrophy of chondrocytes at the epiphyseal plates
- remember, these plates will lengthen bone via interstitial growth as the chondrocytes within the interior of the bone divide

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5
Q

what happens when there is excess of GH?

A
  • children: gigantism
  • adults: acromegaly
  • usually have adenoma of the anterior hypophysis (anterior pituitary) that is responsible for hypersecretion of GH
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6
Q

what can predispose to adenoma formation?

A

a mutation in the gene encoding the aryl hydrocarbon-interacting protein

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7
Q

overall, what does IGF-1 do in this context?

A

stimulates growth of long bones by stimulating the hypertrophy of chondrocytes at epiphyseal plates

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8
Q

describe the overall cycle of GH

A
  • anterior pituitary secretes GHRH
  • GHRH acts on acidophil cell in anterior pituitary, causing it to secrete GH
  • GH acts on the liver, making it secrete IGF-1
  • IGF-1 stimulates hypertrophy of chondrocytes at epiphyseal plates, thus stimulating growth of long bones
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9
Q

negative control of GH

A

somatostatin and elevated blood glucose inhibit GHRH from binding acidophil cells in anterior pituitary so they can’t make GH

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10
Q

IGF-1 in blood and bone

A
  • first of all, the liver is the major source of IGF-1 in circulation
  • in blood, IGF-1 circulates on an IGF-binding protein
  • in bone, GH, PTH, and estrogens all stimulate IGF-1 release
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11
Q

GH acute effects

A
  • within minutes to hours
  • anti-insulin metabolic effects
  • GH binds to a specific tyrosine kinase-associated receptor that is related to several cytokine receptors on the surface of many target tissues
  • it basically antagonizes the hepatic and peripheral effects of insulin. this means too much GH can cause hyperglycemia
  • this decreases glucose metabolism and increases blood glucose
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12
Q

GH chronic effects

A
  • long-term growth-promoting effects
  • stimulate production of IGF-1
  • GH binds to a specific receptor tyrosine kinase that is structurally related to the insulin receptor, so mimics insulin
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13
Q

describe growth in length of long bones

A
  • depends on interstitial growth of epiphyseal growth plates (hyaline cartilage)
  • remember, interstitial growth is growth from the inside
  • this happens as the center of the cartilage gets replaced by bone
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14
Q

what forms the primary ossification center?

A

vascularization of the bone collar and hypertrophy of diaphysial chondrocytes

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15
Q

what happens after the primary ossification center is formed?

A
  • blood vessels enter the newly formed medullary cavity and grow towards the epiphyseal ends of the bone, forming the two epiphyseal growth plates
  • the whole bone can elongate when chondrocytes of the epiphyseal growth plates proliferate and become hypertrophic
  • in adults, the cortical bone gets to its full length and width, and when this happens the epiphyseal plates become ossified (closed), forming the epiphyseal line
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16
Q

four major zones of endochondral ossification

A
  • reserve zone (closest to epiphysis)
  • proliferative zone
  • hypertrophic zone
  • vascular invasion zone (closest to diaphysis)
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17
Q

reserve zone

A
  • primitive hyaline cartilage responsible for growth in length of the bone as erosion and bone deposition advance (“chase”) into this zone
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18
Q

proliferative zone

A

proliferating chondrocytes align as vertical and parallel columns

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19
Q

hypertrophic zone

A

apoptosis of chondrocytes and calcification of territorial matrix (basically, cartilage ec matrix gets calcified, becoming bone tissue)

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20
Q

vascular invasion zone

A
  • blood vessels penetrate and transverse calcified septa, carrying osteoprogenitor cells with them
  • these osteoprogenitor cells will differentiate into osteoblasts, which will eventually become osteocytes when they get stuck in the matrix that they secrete
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21
Q

describe the perichondrium

A
  • this is the outermost layer of the cartilage
  • eventually turns to periosteum
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22
Q

describe the periosteum

A
  • has an outer “fibrous layer”
  • has an inner “osteogenic layer” that has progenitor cells that develop into osteoblasts
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23
Q

what is the overall purpose of IGF-1?

A
  • it is the primary stimulator of chondrocyte activity and ultimately bone growth
  • insulin and thyroid hormones also provide an additional stimulus
24
Q

describe different areas of growth at different ages

A
  • brain grows first and fast
  • they body height grows, stops during childhood, and spikes during puberty
  • reproductive organs are stagnant and spike during puberty
  • see graph of this on slide 10
25
Q

what influences steep growth during adolescence?

A
  • sex steroids
  • the major growth-promoting effect of sex steroids is to stimulate secretion of GH and IGF-1
26
Q

difference between GH and sex hormones

A

unlike GH, sex hormones stimulate bone growth but also stop it by inducing epiphyseal closure

27
Q

describe the different hormones involved in bone growth

A
  • growth of epiphyseal growth plate cartilage is regulated by IHH
  • IHH is secreted by proliferating chondrocytes and stimulates cells of the chondrogenic layer of the perichondrium to secrete PTH-rP
  • PTH-rP stimulates chondrocyte proliferation (but not differentiation, so it delays hypertrophy)
  • IHH basically maintains pool of proliferating chondrocytes in the growth plate by delaying their hypertrophy via pTH-rP
28
Q

recall what the chondrogenic layer of the perichondrium is

A
  • undifferentiated cells on the interior of the perichondrium (outer layer of cartilage)
  • these cells can differentiate into chondroblasts and eventually chondrocytes
29
Q

describe the feedback loop between IHH and PTH-rP

A

add this after asking professor

30
Q

what does lack of expression of IHH protein in mutant mice lead to?

A
  • dwarfism
  • lack of endochondrial ossification
31
Q

what is the concept used to describe bone growth in length?

A
  • osteoclastic “chase”
  • chondrocytic “run”
32
Q

describe the steps of the growth process at the epiphyseal growth plate

A
  • calcification of cartilage
  • osteoid deposition and calcification
  • osteoclasts chase and invade the zone previously occupied by the chondrocytes
  • the ossification front moves
  • bone grows in length
33
Q

on slide 11, there are three steps in the growth process: describe them

A
  1. ossification front invades and destroys the chondrocytes and passes through the site previously invaded by the chondrocytes
  2. calcification of the cartilage matrix surrounding hypertrophic chondrocytes
  3. proliferating chondrocytes away from the ossification front increase the length of the cartilage
34
Q

what growth factor stimulates the formation of blood vessels?

A

vascular endothelial growth factor (VEGF)

35
Q

role of osteoprogenitor cells in this growth process

A
  • firstly, these cells are derived from the perivascular mesenchyme
  • they reach the primary ossification center (via the blood) and generate osteoblasts
36
Q

describe the role of osteoclasts

A
  • these are derived from monocytes
  • they enlarge the bond marrow cavity
  • overall, regulate how much bone is made by degrading some bone as it gets built
37
Q

what stimulates/inhibits the transition from mature chondrocyte to hypertrophic chondrocyte?

A
  • stimulates: Cbfa/Runx2
  • inhibits: Sox9
38
Q

what is periosteum?

A
  • membrane that covers outer surface of all bones, except at the joints of long bones
  • outer “fibrous” layer with fibroblasts and dense irregular connective tissue
  • inner “osteogenic layer” containing progenitor cells that develop into osteoblasts
39
Q

what is endosteum?

A

lining of the inner surface of all bones

40
Q

review the hormone chart on slide 10

A

DO IT

41
Q

appositional growth

A
  • as bone grows in length, new layers of bone get added to the outer portions of the diaphysis, enlarging the diameter of the bone
  • bone increases in width by cycles of appositional deposition and resorption of compact outer lamellar and osteonal outer bone as well as of cancellous bone
  • as these cycles of deposition and removal occur, the marrow cavity enlarges by removal of bone at the endosteal surface
  • new bone in the form of haversian systems gets added beneath the periosteum by its osteogenic layer
42
Q

important note on ossification

A
  • ossified bone matrix grows only by appositional mechanism
  • this is regardless of whether it initially formed via intramembranous or endochondral ossification!!
43
Q

look at the chart on the bottom left on slide 12

A

specifically make sure to know the osteoprotenitor to osteoblast to osteocyte transition!!

44
Q

describe ossification when IGF-1 is present

A
  • this is normal
  • epiphyseal plate is normal size, can see hypertrophic zone
45
Q

describe ossification when IGF-1 is absent

A
  • this is abnormal
  • reduction in width of the hypertrophic zone results in a 30% decrease in the longitudinal growth of the bone
46
Q

laron syndrome

A
  • aka laron-type dwarfism
  • autosomal recessive
  • characterized by an insensitivity to GH
  • caused by variant in the GH receptor due to mutations in the gene for the receptor
  • can result in defective hormone binding to the ectodomain (part going into extracellular space) or reduced efficiency of dimerization of the receptor after hormone occupancy
  • basically, GH binding will not cause its normal cascade
  • IGF-1 levels are very low as well as IGF-binding protein 3 (the principle carrier protein for IGF-1)
  • causes short stature and resistance to diabetes and cancer (SO HAS SOME BENEFITS) these people are very sensitive to insulin
47
Q

achondroplasia

A
  • most common disease of the growth plate, big cause of dwarfism
  • autosomal dominant (homozygous is fatal)
  • mutation in fibroblast growth factor receptor 3 gene
  • these mutations are in sperm and are usually spontaneous, so they increase with paternal age because sperm have had more chances to divide
  • causes impaired proliferation of cartilage at the growth plate, which prevents endochondral ossification
48
Q

clinical findings in achondroplasia

A
  • normal-sized to enlarged head, trunk is mostly normal length
  • short arms and legs
  • skeletal abnormalities usually don’t affect longevity, reproduction, intelligence
  • normal levels of GH and IGF-1
  • no treatment
49
Q

discuss achondroplasia and signaling

A
  • this disease is a defect in paracrine signaling
  • manifestation is decreased proliferation of chondrocytes in growth plate
  • usually, the FGFR3 gene (the mutated one here) inhibits cartilage proliferation
  • in achondroplasia, the mutation causes the receptor to be constantly activated, which suppresses growth
50
Q

morphology of achondroplasia

A
  • appositional intramembranous bone formation is not disrupted
  • so bones look thickened in comparison to their short length
51
Q

are adenomas functional or nonfunctional?

A
  • can be either!
  • nonfunctional adenomas can still distort overlying brain
52
Q

what do functional somatotroph adenomas cause?

A
  • first of all, somatotrophs are a cell type in the anterior pituitary
  • cause excess GH secretion
  • monomorphic tumors (made of one cell type) could impair other cell types. for example, pre-pubertal GH tumors can impair gonadotrophs and epiphyseal plates could continue to grow
53
Q

how is GH normally secreted?

A
  • in pulses throughout a 24-hour sleep-wake period
  • peak secretion is in the first 2 hours of sleep
  • a GH-secreting adenoma does not show the typical pulsatile secretory pattern –> instead, it will be elevated and constant, so non-pulsatile
54
Q

how to diagnose a GH-secreting adenoma?

A
  • measure GH in the blood
  • GH secretion is pulsatile, so a single blood measurement doesn’t really tell us anything
  • should measure glucose by mouth and measure GH an hour later to see if glucose could suppress GH as it should
  • in patients with somatotrophic adenomas, GH levels do not get suppressed by glucose, and may actually rise
  • can also just measure IGF-1 instead of GH
55
Q

gigantism vs acromegaly

A
  • gigantism: too much GH in children
  • acromegaly: too much GH in adults
  • in most cases, GH hypersecretion is caused by an adenoma in the anterior pituitary
56
Q

what does excess GH during childhood and puberty cause?

A
  • linear (length) and periosteal (width) growth of long bones
  • cartilage, membranous bones, and soft tissues can also be affected
  • this is gigantism
57
Q

what does excess GH after puberty cause?

A
  • acromegaly
  • long bones do not grow in length, but cartilage and membranous bones continue to grow
  • soft tissues become enlarged
  • can lead to circulatory failure because too much GH and IGF-1 eventually causes structural changes to the heart
  • review pic of manifestations on slide 17

BMS 460 (34 decks)

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