Lecture 32 Flashcards
What does growth hormone trigger hepatocytes to release?
Insulin-like growth factor-1 (IGF-1)
What cells release IGF-1?
Hepatocytes
Where are hepatocytes located?
Liver
GHRH targets what cell to release growth hormone?
Acidophil cells
Where are acidophil cells located?
Anterior pituitary gland
What 2 factors inhibit growth hormone release?
- Somatostatin
- High blood glucose
What does IGF-1 stimulate the growth of?
Growth of long bones
How does IGF-1 stimulate its target cells?
IGF-1 stimulates the hypertrophy of chondrocytes at the epiphyseal plates (line at each end of bone)
What two diseases does excess growth hormone cause?
- Gigantism in children
- Acromegaly in adults
What is the major cause of growth hormone hypersecretion?
Adenoma of the anterior hypophysis
What often causes adenoma formation?
Mutation in the gene encoding the aryl hydrocarbon-interacting protein
What is the acute effect of growth hormone?
Anti-insulin metabolic effects
How are the acute effects of growth hormone brought about?
Growth hormone binds to a tyrosine kinase-associated receptor which is related to several cytokine receptors on the surface of multiple target tissues.
This antagonizes the hepatic and peripheral effects of insulin on glucose metabolism as a defense against hypoglycemia
Why would it be important for growth hormone to act as an insulin antagonist?
If a person is growing, more cells require glucose. Insulin will lower serum glucose levels. The combination of these events can lead to hypoglycemia.
What is the chronic effects of growth hormone?
Growth producing effects via stimulating production of IGF-1
How are the chronic effects of growth hormone brought about?
Through binding to a specific tyrosine kinase that is structurally related to the insulin receptor.
What is the receptor that growth hormone will bind to?
Tyrosine kinase-associated receptor (acute) or tyrosine kinase receptors specific to growth hormone (chronic)
What is the order that hormones and factors are used, and where, in the process of growing long bones?
- GHRH (hypothalamus)
- Growth Hormone (acidophil cells of anterior pituitary gland)
- IGF-1 (hepatocytes of liver), which end up binding to tyrosine kinase receptors on the epiphyseal plates of long bones
How does a drop in serum levels of IGF-1 or glucose effect growth hormone levels?
Both will stimulate growth hormone release
- Lowered IGF-1 means that growth cannot occur, which triggers GH release to stimulate IGF-1 release
- Lowered glucose levels means a risk of hypoglycemia, which stimulates GH release in order to inhibit insulin activity by acting as an insulin activity.
What are the 4 major zones of endochondral ossification?
- Reserve zone
- Proliferative zone
- Hypertrophic zone
- Vascular invasion zone
What is the reserve zone?
- The zone between the epiphyseal cartilage and proliferative zone
- Made up of primitive hyaline cartilage responsible for growth in length of the bone
What is the proliferative zone?
- The zone between the reserve zone and the hypertrophic zone
- Site of proliferating chondrocytes which align as vertical and parallel columns
What is the hypertrophic zone?
- The zone between the proliferative zone and the vascular invasion zone
- The zone where apoptosis of chondrocytes and calcification of the terroritorial matrix occurs
What is the vascular invasion zone?
- The final zone of endochondral ossification
- The zone where blood vessels penetrate the transverse calcified septa and carry osteoprogenitor cels with them.
What is periosteum?
The membrane around the bone
What is the structure of the periosteum?
- Outer fibrous layer with fibroblasts and dense irregular connective tissue
- Inner osteogenic layer that contains progenitor cells that develop into osteoblasts
What structure turns into periosteum?
Perichondrium
What is perichondrium?
Similar to periosteum, but surrounds the cartilage in the body. Turns into periosteum when cartilage ossifies in bone growth
What is the epiphyseal growth plates made of?
Hyaline cartilage
What is cartilage in bones replaced by?
It is replaced by bones via ossification
What is the primary ossification center?
This is the first area where bone formation begins, located in the middle of the diaphysis of long bones
What forms the primary ossification center?
Vascularization of bone collar and hypertrophy of the diaphyseal chondrocytes
Where is bone first developed from cartilaginous chondrogenic cells?
Primary ossification center in the diaphysis
What does the primary ossification center create within the bone?
Medullary cavity
What is the medullary cavity?
The hollow area of the bone that allows for vascularization.
How are the epiphyseal growth plates formed?
Blood vessels enter the medullary cavity and grow toward the epiphyseal ends of the bone.
What happens to the epiphyseal plates when the bone achieves full length at adulthood?
The epiphyseal plates become ossified and called the epiphyseal line
Other than IGF-1, what hormones provide additional stimulus to bone growth?
Insulin and thyroid hormones
What causes the major growth during adolescence?
Sex steroids
How do sex steroids stimulate bone growth?
Stimulating secretion of GH and IGF-1
What is the secondary effect of sex hormones on bones?
Inducing epiphyseal closure and creating the epiphyseal lines
What is the life stages of chondrocytes in ordre?
- Prechondrocyte (chondrogenic layer of perichondrium)
- Early chondrocyte (Proliferating chondrocytes)
- Maturing chondrocyte (Hypertrophic chondrocytes)
What protein is secreted by proliferating chondrocytes to regulate epiphyseal growth plate cartilage growth?
Indian Hedgehog Homolog (IHH)
What protein does Indian Hedgehog Homolog stimulate?
Parathyroid hormone-releated peptide (PTH-rP) from the chondrogenic layer of the perichondroium
What does parathyroid hormone-related peptide stimulate?
Chondrocyte proliferation and delays their hypertrophy
What hormone maintains the pool of proliferating chondrocytes?
IHH
How does the pool of proliferating chondrocytes stay maintained?
IHH delays the hypertrophy of chondrocytes by stimulating PTH-rP
What does a lack of expression of IHH protein result in?
Dwarfism and lack of endochondral ossification
As chondrocytes mature, what happens to the concentration of IHH?
It increases
As chondrocytes mature, what happens to the concentration of PTH-rP?
It decreases
What is the major concept of bone growth?
Osteoclasts “chase” and chondrocytes “run”
What are the processes that happen during bone growth?
- Calcification of cartilage
- Osteoid deposition and calcification
- Osteoclasts chase and invade the zone previously occupied by chondrocytes
- The ossification front moves
- The bone grows in length
What is the direction of growth, starting at the innermost zone of endochondral ossification?
- Vascular invasion zone
- Hypertrophic zone
- Proliferative zone
- Reserve zone
- Epiphyseal cartilage
What actions happen in the vascular invasion zone for growth?
- Vascular Endothelial Growth Factor (VEGF) promotes further growth of vasculature
- Osteopregintor cells, derived from perivascular mesenchyme, reach the primary ossification center and generate osteoblasts
- Osteoblasts begin to deposit osteoid along the calcified cartilage. The osteoid calcifies
What action happens in the hypertrophic zone for growth?
Chodrocytes become hypertrophic as the ossification front approaches
What action occurs in the proliferative zone?
Proliferative chondrocytes start expressing Cbfa1/Runx2 transcription factor
What is the purpose of Cbfa1/Runx2?
Transition from mature chondrocyte to hypertrophic chondrocyte
What inhibits the transition from mature to hypertrophic chondrocyte?
Sox9
What are the steps in bone growth according to the “chase”/”run” model?
- Osteoclasts “chase” (derived from monocytes, enlarge the bone marrow cavity)
1. Ossification front invaades and destroys the chondrocytes and passes through the site previously occupied by chondrocytes
2. Calcification of the cartilage matrix surrounding hypertrophic chondrocytes
3. Proliferating chondrocytes away from the ossification front increase the length of the cartilage - Chondrocytes “run”
What is the growth type that widens the diaphysis?
Appositional growth
In what way does the ossified bone matrix grow?
Appositional growth only
In what way does the ossifed bone matrix form?
Via endochondral and intramembranous growth
How does intramembranous growth differ from endochondral growth?
- Intramembranous ossification directly develops bone from mesenchymal connective tissue
- Endochondral ossification develops bone by replacing hyaline cartilage
How does appositional growth occur?
Through appositional deposition and resorption of compact outer lamellar and osteonal outer bone as well as cancellous bone
What is lamellar bone?
Refers to organized, sheet-like structure of bone tissue
What is osteonal outer bone?
Refers to the compact bone made up of cylindrical units called osteons
What is cancellous bone?
Refers to the spongy inner bone tissue with honeycomb-like structure
What happens to the marrow cavity as appositional growth occurs?
Cycles of deposition and removal enlarge the marrow cavity, via removal of bone at the endosteal (inner) surface.
Where are bones added in appositional growth?
Bone is added in the form of Haversian systems and added beneath the periosteum by its osteogenic layer.
What is endosteum?
Lines the inner surface of all bones, much like periosteum on the outer surface.
Where does periosteum not cover on bones?
The joints of long bones
How is ossification affected when IGF-1 is absent?
There is a reduction in width of hypertrophic zone and about a 30% decrease in longitudinal growth of bone.
What is Laron syndrome?
A type of dwarfism; Autosomal recessive disorder characterized by an insensitivity to GH.
What causes Laron-type dwarfism?
A variant of the GH receptor- mainly associated with mutations in the gene for the GH receptor.
How does a mutation in GH receptor affect physiological conditions?
- Defective hormone binding to the ectodomain (part that sticks off a cell)
- Reduced efficiency of dimerization of receptor after hormone occupancy
What proteins are in low concentration with Laron syndrome?
- IGF-1
- IGF-binding protein 3 (principal carrier protein of IGF-1)
How does Laron syndrome present?
- Short stature
- Resistance to diabetes and cancer
What is achondroplasia?
Most common disease of growth plate and a major cause of dwarfism; Autosomal dominant disease, with homozygous cases being fatal
What is the pathogenesis of Achondroplasia?
- Mutation in Fibroblast Growth Factor Receptor 3 gene
- Impaired proliferation of cartilage at the growth plate -> preventing endochondral ossification
How do mutations in FGFR3 gene come about?
About 80% are new spontaneous (de novo) mutations, with the odds of occurance increasing with paternal age.
How does Achondroplasia present?
- Normal-large head and trunk of normal length
- Shortened arms and legs
- Normal levels of growth hormone and IGF-1
How does Achondroplasia effect quality of life?
If not a homozygous case, no change in longevity, intelligence or reproductive status are noted
What is the treatment for Achondroplasia?
There is no treatment.
How does the mutation of FGFR3 cause the growth suppression?
Shows up as a defect in paracrine cell signaling as a constantly activated FGFR3 will continuously inhibit cartilage (chondrocyte) prolieration
Morphology of Achondroplasia
Appositional intramembranous bone formation is not disrupted -> cortices form normally and appear thickened in relation to the short length
How is growth hormone released into the blood in physiologic conditions?
Pulses throughout a 24-hour sleep-wake period, with peak secretion occurring during the first two hours of sleep.
What is the effect of a functional somatotroph adenoma on the pituitary gland?
Hypersecretion of GH
Monomorphic tumors only affect one cell type
FALSE - for example, GH tumors can impair gonadotrophs.
If a patient has a GH-secreting adenoma, how is the pulsatile release affected?
The tumor consistently secretes at a high level and is no longer pulsatile.
How is GH-secreting adenomas diagnosed?
By measuring GH levels in blood to test if it is pulsatile and testing the reaction with glucose.
How does testing GH levels in blood with glucose diagonose for GH-secreting adenoma?
In physiologic conditions glucose suppresses GH, but patients with adenomas actually may paradoxically rise
How can you make sure abnormal GH levels aren’t just an error?
You can compare with the IGF-1 values. Both in physiologic and nonphysiologic conditions, IGF-1 should be following the same trend as GH.
What is affected in Gigantism?
- Linear and periosteal growth of long bones increased.
- Cartilage growth increased.
- Membranous bones increased growth.
- Enlarged soft tissues.
What is affected in Acromegaly?
- Linear and periosteal growth of long bones not affected.
- Cartilage growth increased.
- Membranous bones increased growth.
- Enlarged soft tissues.
How are lab results affected when a patient suffers from Acromegaly?
- Increased GH
- Increased IGF-1
- Increased insulin
- increased calcium and phosphate
- Increased Glucose
- Increased or decreased ACTH
