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Lecture 2

Physiology 3120 Lecture Notes - Lecture 2: Apoptosis, Normal Matrix, Bone Resorption

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Tom Stavraky

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Physiology 3120
Dr. Woods
Lecture 2
Composition and Organization of Bone
- Different bones underwent different processes in order to be developed
- Ex: long bones were formed by endochondrial ossification
- Ex: bones of sternum and bones of skull were formed by intramembraneous ossification
Endochondral Bone: Cartilage Template Formation
- If this was a future femur, we first form a cartilage template
- In utero, in very early development, we get a cartilage template that is formed first
- So mesenchymal cells differentiate into chondrocytes
1. Chondrocytes secrete an extracellular matrix containing type II collagen and proteoglycans
o Almost identical to articular cartilage
2. Chondrocytes in the center of the template differentiate to hypertrophic chondrocytes
o Hypertrophic chondrocytes are larger as they are increasing in size and they are
differentiated they are maturing from a chondrocyte
3. Hypertrophic chondrocytes secrete type X collagen and less proteoglycans
o Type X collagen is unique in that it is found in the hypertrophic region where we have
hypertrophic chondrocytes
o Collagen provides strength while proteoglycans provide cushion
o So when we have more collagen, there is more strength to the matrix and a little bit less
of a compression/squishability of the matrix
o the goal is to increase the strength (this is happening where the hypertrophic
chondrocytes are at the very center of the template)
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o up until this point, these chondrocytes (which are pretty metabolically active) have
been receiving nutrition from diffusion (O2 comes in, glucose is just diffusing through
the ECM template)
o but at some point, hypoxia develops bc the template gets too big
4. Localized hypoxia (decreased O2) in the hypertrophic zone triggers secretion of angiogenic
factors(VEGF), recruitment to hypertrophic chondrocytes
o VEGF is a vascular endothelial growth factor it’s a angiogenic factor (molecule that
will stimulate the recruitment of blood vessels
o This is a good thing bc the cells are currently hypoxic, requiring more nutrition and O2,
we want to deliver a blood vessel to this region to provide the appropriate nutrition for
these metabolically active cells
5. Hypertrophic chondrocytes mineralize the surrounding matrix and undergo apoptosis
o Hypertrophic chondrocytes have a job to not only to secrete that type X collagen matrix
(which is more rigid) but to also mineralize the matrix
o Up until this point, the matrix has been organic, its been collagen and proteoglycans
o Mineralization is the secretion of Ca2+ and phosphate (the inorganic salts)
o This mineralization provides further rigidity to the ECM
o Then the hypertrophic chondrocytes die undergo apoptosis, leaving behind the
mineralized matrix they have produced
6. Invading blood vessels bring in osteoclasts and permit entry of osteoblasts to this mineralized
zone (primary ossification)
o At the same time as step above, we have blood vessels recruited to the hypertrophic
o Invading blood vessels come into the region of hypertrophy and bring in with them
osteoblasts and osteoclasts
o Osteoblasts reside in the blood
o Osteoclasts are a type of monocyte(macrophage) that differentiates into a osteoclast
So osteoclasts are a type of macrophage
o Within the blood, osteoclasts come in and permit the entry of osteoblasts bc on
the periphery of the cartilage template, there are osteoblasts (which cant get
into a cartilage template unless blood vessels make way)
o So blood vessels provide a path for the osteoblasts to follow externally
o Note: osteoblasts don’t enter the blood, they travel alongside the vessels
o Osteoclasts are bone breaking down cells but in this case, osteoclasts are going
to start to degrade the cartilage matrix
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7. Osteoclasts remove the hypertrophic chondrocyte extracellular matrix
o In the center region, where the blood vessels have invaded, our osteoclasts can leave
the blood vessels and remove the hypertrophic ECM
o So they degrade like a macrophage but they are degrading the matrix that the
hypertrophic chondrocytes produce
8. Osteoblasts replace the cartilage matrix with osteoid (mostly type I collagen) and then
mineralize it (hydroxyapatite)
o Osteoid is the organic component of bone
o So the osteoblasts first secrete the organic matrix and then it secretes the Ca2+ and
phosphate which will provide the mineral inorganic component of bone
o Ca2+ and phosphate together in a mineral form is called hydroxyapatite
9. Chondrocytes on either side of the primary ossification centre are still actively proliferating
o On either side of this replaced template, we still have chondrocytes (blue cells) which
are still producing a cartilage matrix
o The center region is called the primary ossification center (the middle of the template
that has just been replaced by bone tissue)
o In humans, primary ossification happens at 12 weeks gestation (the darker areas in the
pic on the right are the primary ossification center)
o Note: in different species primary ossification centers form at a different rate
10. Secondary ossification occurs in both condyles (epiphysis). In humans, mostly occurs
o Secondary ossification occurs at either end of the bone in the cartilage template
o Same process occurs: center region becomes hypoxic, the hypertrophic
cells that are differentiating from chondrocytes secrete VEGF, we get
recruitment of blood vessels and then mineralization of matrix and those
hypertrophic chondrocytes die
o Then osteoclasts come in, remove the matrix then osteoblasts come along
side and replace that matrix with an osteoid which is then mineralized
o Secondary ossification in most of your bones happens postnatally (after
you are born)
o When you are bone, youre mostly primary ossified then your bone starts
to form secondary ossification centers
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