april 23 how bones grow....

Bone: osteoid (collagen and other proteins)
hydorxyabpatite crystals (CaPo4) are the crystals found in bones.

If you look at the cross section of bone, the head part is the epiphysis, and the narrow part is the diaphysis, and is divided by the epiphsyeal plate (made of cartilage: collage and polysacarides) In order for bone to grow the cartilage plate expands (gets thicker), and as the epiphaseal plate thickens it pushes the head of the bone moves upward, and the cartilage is replaced by bone. Without the epiphyseal plate, you can't get growth. This method means that the bones get longer at each end. (only in long bones that have the epiphyseal plate) (bones in the skull grow by a different method)

The last thing you need to know before we look at this in more detail...
the cell types for making bone: osteoblasts, secrete osteoid (proteins) and enzymes that increase precipitation of calcium. (ca2+ to form CaPO4)
and osteoclasts are involved in bone RESORBTION, they produce enzymes that dissolve bone, and clean things up. They are developmentally related to macrophages.
and for making cartilage: chondrocytes, secrete collage, and polysacarides together make cart.


At the bottom part of the bone figr 18.16, you need to add a layer of cells that is below and immediately below the epiphysis is the progenitor chondocytes. They give rise to chondrocytes. They are stimulated to differentiate into chondrocytes. then the chondrocytes proliferate and each gets bigger and bigger. The secrete and lay down cartilage in this process. They organize themselves into columns in the direction of bone growth. Once th echondrocytes are mature, they stop growing and are totally surrounded by the cartilage, and the nutriants can't get through, and their lifespan is limited. When the chondrocytes start to die the osteoclasts clean up the mess and are replaced with osteoBLASTS, and they lay down new bone. This process continues in cycle so that the end of the bone gets pushed farther and farther from the diaphysis. each cartilage plate can only make a certain amount of chondrocytes, and then the cartilage is all replaced with bone, and growth stops. (regulated by sex hormones)

Calcified cartilage is not yet bone, but it is a step in the bone growth, by it being digested by the osteoCLASTS, and osteoBLASTS come in to replace with bone. The chondrocytes have to be in columns or growth won't happen efficiently.

GROWTH HORMONE:
stimulates differentiation of progenitor chondrocytes to chondrocytes and it stimulates proliferation of chondrocytes, and it stimulates proliferation and activity of osteoBLASTS. You need both hormones to do the job: IGF-1 raise ccchondrocyte prliferation and hypertrophy (enlarge). also raises osteoblast proliferation and activity. if a person is missing either, then long bone growth doesn't occur at the normal rate (greatly diminished). (IGF-1 is locally produced dependant upon the presence of GH (growth hormone) (IGF-1: insuline growth factor 1)

hypothyroid means that you don't grow, it has a direct effect on bone.
T3, T4: increase GH secretion, and increase GH receptor expression, and raise proliferation and hypertrophy of chondrocytes, and they are needed for normal columnar organization of the chondrocytes in the epiphyseal cartilage.

At puberty the epiphyseal plate disappears and growth stops. they think it is due the the activation of estrogens. (the epiphyseal plate 'closes', which means the cartilage is gone) It is due to loss of stem cells that give rise to chondrocytes and this process is accelerated by estrogens.

andgrogens in men are converted to estrogens and does the same thing. without andgrogen/estrogen receptors then the people get very tall, because it takes so much longer for the process to happen.

GH, IGF1, also increase bone width by increasing the activity of osteoblasts which lay down new bone around the sides of the bone... this continues after puberty.

The effects on intermediary metabolism. We won't worry about IGFs in terms of the intermediary tmetabolism. (sometimes they are opposite too, so it is super confusing, just forget about it in regards to int. met) just pay attention to the GH.

GH effect lipid/carbohydrate metabolism, protein metabolism, and ______ metabolism.
protein metabolism is relate to growth, by increasing protein synth, and aa uptake into cells, increases RNA synth, which goes along with protein synth, and inhibits proteolysis.

Lipid and carb metabolism:

the nervous sysstem requires glucose as its major energy. without it you go into coma. there are mechanisms to make sure it never gets to low. the approach that GH uses to control is that it regulates pathways and intermediate met that conserves protein. it provides through these actions, it provides fuels that can be used in place of AAs, because you don't want to process the AAs to make glucose. the major ways the body does that is by breaking down muscles through gluconeogenesis to get AAs into glucose. But that is bad. GH prevents this process. instead it raises blood glucose levels in a way that protects the proteins in the bodies, so that they don't get turned into glucose.

if we look first at lipid metabolism...GH increases lipolysis (triglycerides are hydrolized into fatty acids + glycerol). the fatty acids can be used as an energy source by cells outside the central nervous system. This spares glucose for use by the CNS. (muscles use the fatty acids INSTEAD of the glucose, so the glucose is left free for the CNS to use instead.
glycerol is a substrate for gluconeogenesis (glycerol can be turned into glucose).

carb metabolism: effects on carb met... GH decreases glucose uptake by cells outside of the CNS. decreases glucose use (decreases glycolosis). stimulates gluconeogenesis. all of these act to increase the glucose concentration of the blood. People discribe these effects as 'increasing insulin resistance'. you need to know that insulin does the exact opposite of what GH does. It acts to get glucose out of blood. (gluconeogenesis: making glucose from some other substrate... glycolosis backwards) If you have too much GH it takes FAR MORE insulin to lower the blood glucose levels.

You want proteins to be protected. They are inhibit from use of glucose with GH.

REGULATION OF GH SECRETION:
Look at handout for basic feedback loop.

There are to hypothalic:
GHRH and somatostatin.

GHRH is 44AAs.
somatostatin is 14 AAs.
They are both fairly short peptides. they are probably going to be secretes as proforms. they are made by different population in the hypoth. in terms of their mech of action. both types of recptors are serpatine. serpantine recpetors are coupled to G-proteins.
GHRH is coupled to G(sub S) (increases cAMP)
sinatistatin is coupled to G(sub i) (decrease cAMP)

as cAMP increase leads to calcium entry into the cell, and the increase in calcium(Ca2+) stimulates exocytosis of GH.

GHRH vs somatostatin are reciprocal. if you totally disconnect the pit from the hypth, the net action is a decrease in GH secretion.

GHRH is the more dominant/controlling factor. they both together regulate GH secretion.

At the bottom of the handout are other factors that regulate GH secretion.

Similar control as thyroid hormones.

Conditions that stim secretion:
hypglycemia, fasting; raise plasma AA (esp arg); prolonged caloric deprivation; acute stress; exercise; puberty (estrogens/androgens); sleep.

Conditions that inhibit secretion: hyperglycemia (raises fatty acids); hypthyroidism; aging; emotional deprivation; raised cortisol for extended period of time.