Lecture 35

Bone formation = ossification

-has two steps

1. lay down a matrix called osteoid (90-95% collagen and the rest is a gelatinous called the ground substance)

2. mineralization = laying down of hydroxy apatite (non-soluble)

-just seems to occur, not set up by one particular thing

-all tissue in our body contain compounds that block mineralization

-osteoid does not contain these compounds that block mineralization

-sometimes in old age these compounds break down and you can see muscles turn to bone

-osteoid is made by osteoblasts

-osteoblasts cannot reproduce and they are made by osteoprogenator cells

-once an osteoblast makes an osteoid it can't reproduce

-as an osteoprogenitor cell, they can reproduce and make osteoblasts, but they can't make osteoid

-osteoprogenitor cells live in the osteum (inner lining of bone), periosteum (outer lining of bone), and haversian canals

-in utero bone is made by two methods:

1. intramembranous ossification

-take a sheet of essentially progenitor cells called mesenchyme and the sheet will eventually become the bone

-mesenchyme cells differentiate to become osteoblasts which then deposit osteoid, the osteoid then mineralizes over time

-flat and irregular bones form this way

2. endochondral ossification

-when hear chondro should be thinking has something to do with hyaline cartilage

-hyaline cartilage forms the shape of a bone and then the osteoblasts will deteriorate and destroy the hyaline cartilage and replace it with osteoid

-short and long bones are created by this process

-osteoid production continues until the articular and epiphyseal cartilage is left

-chondroblasts building the outside, osteoblasts are eating the inside and replacing it with bone

-osteoblasts build the bones

-osteocytes = function as bone cells, when an osteoblast gets trapped in the bone and builds so much osteoid around it that it gets trapped, then it is called an osteocyte and will remain there forever, function as bone cells

-flat bones grow at periphery by intramembranous ossification

-long bones grow at ends

-chondrocytes = hyelin cartilage was built by chondroblasts which become chrondrocytes when we them in hyelin cartilage, get traipped in the hyaline cartilage

-thickening of the bone is done by intramembranous ossification

-as gets thicker on outside via intramembranous ossification, osteoclasts will eat out the inside so they are light

-bone growth regulated by insulin-like growth factor 1

-growth continues until the epiphyseal cartilage closes, can see this on an x-ray

-osteoblasts build osteoid which mineralizes to bone

-osteoclastss tear bone down

 
 

Remodeling:

• osteoblasts/osteoclasts important for bone remodeling
  
• bones are very dynamic and the remodeling process is important for repairing minor cracks that occurred in mineralization, but as part of the stress on the bone the collagen that is laid down, during stressful activities some of the collagen bonds have been broken, so you're replacing old collagen with new collagen (that has solid bonds) and doing minor crack repair
  
• remodeling will reshape
  
  • strength of the bone = collagen
    
  • hardness of the bone = mineralization
    
• remodeling can do shape changes in response to stress (bone can thicken and become thin)
  
• bone grain (which way haversian canal is facing) direction can change
  
  • joggers have different patterns to their bones than loggers b/c there are different stresses on the bone
    
• remodeling replaces the distal femur every 5-6 months
  
  • the entire skeleton is replaced 10 times in a lifetime
    
• Involves osteoblasts and osteoclasts
  
  • osteoclasts seal over the tight junctions of the bone
    
  • apical membrane pumps H+ ions in and creates a pH of about 4 and this is the limit and this eats a hole in the bone
    
  • the osteoclasts slowly eats down the hole in the bone and as it dissolves the bone it takes in any Ca and phosphate and will pass them out into the intersitium behind
    
  • it will also pass out an activated TGF-beta (transforming growth factor-beta)
    
    • TGF-beta was in the osteoid and was placed their in an inactive form by the osteoblast
      
    • as the osteoclast ate through the bone it picked up inactive TGF-beta, activated it and kicked it back out to the interstitum
      
    • TGF-beta causes osteoblasts to go down and start to replace the bone with osteoid and will form lacuna (layers, lamella)
      
    • prevents mineralization of the osteoid
      

      -Ca and phosphate goes into the bloodstream b/c it will inhibit mineralization
      

      -at the center of haversian canal have a blood vessel which is stimulated to grow down following the osteoclast
      

      -after it gets down to the bottom the osteoid will start to mineralize automatically and we have changed the shape of the bone and also strengthened the bone
      

      -osteoblasts can activate/prevent the maturation of osteoclasts and therefore the osteoblasts are the major regulators of remodeling
      

      -if an osteoclast is activated it secretes interferon-beta which prevents the activation of other osteoclasts
      

-blood Ca levels are monitored by parathyroid hormone = PTH

-PTH is secreted in response to a drop in blood Ca levels

-PTH is turned off by increased blood Ca levels

-Actions of PTH

1. osteocytes are stimulated to take up exchangeable Ca

-in bone hydroxyl apatite is the major Ca salt in there and it is not soluble, but there are some soluble salts which can be exchangeable

-there is a certain amount of exchangeable Ca that the osteocytes can pass through their cytoplasmic extensions in the canuliculi into the blood, this will stimulate the osteocytes to take up exchangeable Ca and release it into the ECF

2. PTH increases remodeling by direct stimulation of the osteoclasts which releases non-exchangeable Ca

3. increase Ca reabsorption by the thick ascending loops of henle and the distal tubules of the nephron

4. interferes with phosphate reabsorption, increase phosphate secretion

5. increase production of 1, 25 dihydroxycolicalciferol (calicitrol = Vitamin D) by proximal tubules of kidney

-PTH is the sole regulator of blood Ca levels, has a half-life of 20 minutes and then is destroyed by the liver

-in skin have coli calciferol, produced in skin from 70-hydro cholesterol

-skin is in the sunlight and it is the sunlight that changes that to cholicalciferol, once it is produced it circulates to the liver and they add 25 and it becomes cholicalciferol

-this system is pretty much unregulated, but will feedback on itself

-25 dihydroxycaliciferic circulates to the proximal tubule of the kidney where it is taken up and 1-hydroxy is added to make it a di-hydroxy and then its release depends on PTH (stimulated creation/release of 1, 25)

-actions of 1,25 dihydroxcalciferic:

1. facilitates osteocyte pumping of exchangeable Ca

2. causes increase production of Ca binding protein, Calbindin D

-Calbindin D facilitates uptake of Ca by the intestine and the kidney

3. decrease phosphate, but 1,25-dihydroxcalciferic increases the amount of phosphate reabsorption by the kidney

4. stimulates bone remodeling by increasing the number of osteoclasts

-Calcitonin à released by thyroid gland

-What is the stimulus to release calcitonin?

-in mammals is due to the infusion of Ca solutions intravenously

-calcitonin first discovered in fish who change from fresh to salt water

-calcitonin inhibits osteoclasts, stops the release of Ca to the blood, and increases Ca excretion in the urine

-inhibits gastrin, slowing gut to decrease the amount of Ca pushed into the system

-half-life = 10 minutes

-quick but brief reduction of blood Ca levels

-productor rather than a regulator of blood Ca

 
 

Pancreatic Hormones:

Pancreas secretes seceral hormones:

1. Insulin
   
   1. produced by theca cells of the pancreas
      
   2. secreted in response to metabolites entering into pancreatic circulation
      
   3. some CNS regulation
      
   4. metabolites are:
      
      1. glucose, a.a., thetaketo acids
         
   5. parasympathetic --> increase insulin secretion
      
   6. sympathetic --> decrease insulin secretion
      
   7. brain can't regulate the insulin level
      
   8. insulin action occurs at three speeds
      
      1. rapid
         
         1. occur in seconds after being released into bloodstream
            
         2. increase glucose, a.a., and potassium uptake by the cells
            
      2. intermediate
         
         1. occurs in minutes
            
         2. increase protein synthesis (anabolism), decrease protein degradation, increase glycogen synthesis, decrease glycogen breakdown, activates glyolytic enzymes within cells
            
         3. inhibit gluconeogenic enzymes
            
      3. delayed
         
         1. hours later
            
         2. increases lipogenic enzymes