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Flashcards in Bone Dev Histo Deck (29)

Intramembranous Ossification

No hyaline cartilage model precursor
Mesenchyme → Bone

In this process, bone cells (specifically osteoblasts) differentiate directly from mesenchymal cells to produce osteoid.
• The process leads to the production of the flat bones of the skull and the bones of the face.
• This process begins to occur around the 8th week of gestation in humans.


Endochondral Ossification

Hyaline cartilage model precursor
Mesenchyme → Hyaline → Hyaline Cartilage → Bone

In this process, mesenchyme is first replaced by a hyaline cartilage model. Why do we say a hyaline cartilage “model”? We say this because, this the hyaline cartilage takes on the initial shape of the bone, as well as the bone's position in the body. Then, this hyaline cartilage model is eroded and replaced with bone.
• Endochondral ossification leads to the production of most short and long bones of the body.
• During embryonic development in humans, the first hyaline cartilage models are visible in the 6th week of gestation and ossification centers are present in all long bones of the limbs by the 12th week of gestation.


Steps of Intramembranous Ossification

Development of the Ossification Center
3. Woven Bone and Periosteum Development
4. Replacement of Woven Bone


Development of the Ossification Center

Some of the elongated, pale-staining, mesenchymal cells cluster, differentiate into osteoprogenitor cells, and then become more rounded, while their cytoplasm changes from eosinophilic to basophilic. This basophilic change is due to changes in the cytoplasm including the addition of more rough endoplasmic reticulum. These cells have now differentiation into osteoblasts.
• This cluster of osteoblasts



• Calcium and other mineral salts are deposited around the framework of collagen fibers.
• Cells that are trapped in the calcifying osteoid are now called osteocytes and sit in lacunae.


Woven Bone and Periosteum Development

What is being made here is primary bone (also known as woven bone or immature bone).
• This woven bone is produced in small irregularly shaped pieces or spicules that are increased in size by apposition growth (meaning growth along the surface).
• This growth allows the small patches of bone production to merge together to produce a labyrinth of woven bone.
• Then, the spaces between the bone spicules are infiltrated with embryonic blood vessels, which will differentiate into red bone marrow.
• Additionally, the mesenchyme at the periphery of the bone condenses and forms the periosteum.


Replacement of Woven Bone

• The woven bone is then replaced by lamellar bone, forming compact and spongy bone. Specifically, with flat bones, spongy bone will be formed between two layers of compact bone.



loosely organized embryonic connective tissue
This tissue has elongated, pale-staining, undifferentiated cells called mesenchymal cells.
These cells have oval nuclei with prominent nucleoli and fine chromatin.
These cells also have thin cytoplasmic processes.
This tissue is also composed of a viscous ground substance.


small spicules

Starting point for woven bone formation.


Howship’s lacuna

multinucleated cell that is called an osteoclast and is located in a resorption bay, also known as a Howship’s lacuna


Endochondral Ossification steps

1. Development of the Fetal Cartilage Model
• Beginning again with mesenchyme, some mesenchymal cells aggregate and differentiate into chondroblasts. These chondroblasts secrete matrix, including type II collagen, and produce the hyaline cartilage model. This hyaline cartilage model is formed from mesenchyme where the bone is going to form and in a similar shape. This hyaline cartilage continues to grow by interstitial growth due to the activity of chondrocytes located in the lacunae and appositional growth due to the activity of chondroblasts at the surface. This hyaline cartilage model has a surrounding perichondrium.
2. A Bone Collar Forms around the Diaphysis and Cartilage of Shaft Begins to Calcify
• The perichondrium near the mid-region of the cartilage model contains progenitor cells that differentiate no longer into chondroblasts, but instead into osteoblasts. Therefore, this perichondrium is now functionally a periosteum. The osteoblasts that are produced along the surface of the mid-region of the cartilage model secrete osteoid, which is subsequently calcified. This creates a bone collar around the mid-section of the hyaline cartilage model. This bone collar forms along the diaphyseal portion of the developing bone and is the first bone tissue that appears.
• This bone collar begins to impede the diffusion of oxygen and nutrients into the underlying cartilage. This promotes changes.
• The chondrocytes in the mid-region begin to accumulate glycogen, undergo hypertrophy (or, in other words, they swell up), and also produce alkaline phosphatase. These changes compress the matrix and signal the surrounding matrix to calcify. (Keep in Mind: Calcified cartilage is not the same as bone. For example, hyaline cartilage is composed primarily of type II collagen, while bone is composed of primarily type I collagen. With a H&E stain, calcified hyaline cartilage stains blue/purple, while newly formed bone stains pink/red.)
• With the matrix calcified, the chondrocytes can no longer get the nutrients they need, as diffusion cannot take place through the calcified cartilage matrix. Therefore, the chondrocytes subsequently die.
• Without the chondrocytes present, the matrix begins to break down.
• As a result, a porous 3-D structure of calcified hyaline cartilage is created in the shaft or diaphyseal region.


3. Development of a Primary Ossification Center in the Diaphysis

Capillaries and osteoprogenitor cells from the new periosteum penetrate the bone collar and grow into the disintegrating calcified cartilage location inducing the creation of the primary ossification center.
These entering blood vessels into this open space at the core of the diaphysis are important for the development of the bone marrow for the medullary cavity.
Osteoprogenitor cells brought into the area differentiate into osteoblasts. These osteoblasts begin to deposit bone matrix against the remnants of the calcified cartilage. In other words, primary or woven bone is produced along the side of the remaining spicules of calcified cartilage.
Remember, the primary bone is eosinophilic and calcified cartilage is basophilic. The calcified cartilage will also be identifiable as it will cell-less (in other words, it has no chondrocytes present). This is unlike the bone which will have cells (specifically osteocytes) in the lacunae.
Again, this primary ossification center is found in the diaphysis – while at this same time, hyaline cartilage remains in the ends (or epiphyses) of the developing bone.


4. Development of the Secondary Ossification Centers

After birth, secondary ossification centers develop in a similar manner to that of the primary ossification center in the diaphysis. However, these secondary ossification centers are located in the epiphyses.
Chondrocytes in the epiphyses undergoes hypertrophy, the cartilage matrix is compressed, the cartilage matrix calcifies, and the chondrocytes subsequently die – all of which opens up spaces between spicules of calcified cartilage.
Then, blood vessels and osteoprogenitor cells enter the spaces that have been opened up in the epiphyses and secondary ossification centers develop.


5. Retention of Hyaline Cartilage as the Articular Cartilage and the Epiphyseal Plate

Hyaline cartilage is retained on the ends of the model and becomes the articular cartilage for cushioning of bone ends participating in joints.
• Additionally, the remnant of hyaline cartilage between the epiphysis and the flared portion of the diaphysis (known as the metaphysis) is retained as the epiphyseal plate, which will be responsible for the lengthwise growth of long bones.


6. Epiphyseal Plates Ossify and Form the Epiphyseal Lines

At the end of puberty, which marks the end of growth in terms of height, hormone changes cause the epiphyseal cartilage to be replaced with bone forming the epiphyseal line.
The epiphyseal line, therefore, is the remnant of the last location of the epiphyseal plate.


Bone Growth – Length

- Long bones need to increase in length during infancy and youth.
- The process to do so is basically endochondral ossification and occurs in the epiphyseal plate.
- The epiphyseal plate is found between the epiphysis and the flared portion of the diaphysis, known as the metaphysis.
- The epiphyseal plate is composed of hyaline cartilage that can be divided into different zones. The first zone (i.e., the zone of resting cartilage or reserve cartilage) is located next to the epiphysis, while the last zone (i.e., the zone of ossification or zone of resorption) is closest to the diaphysis.


Zones of the epiphyseal plate, starting with the zone closest to the epiphysis, and the activity occurring within each zone:

1. Zone of Resting or Reserve Cartilage
2. Zone of Proliferation or Proliferating Cartilage
3. Zone of Hypertrophy or Hypertrophic Cartilage
4. Zone of Calcified Cartilage
5. Zone of Ossification (you may also see this called the Zone of Resorption or Zone of Remodeling)


1. Zone of Resting or Reserve Cartilage

• Again, this is the zone that is closest to epiphysis.
• In this zone, you will see chondrocytes singularly or in very small groups.
• Basically, nothing exceptional is going on in this zone; there is no active matrix production


2. Zone of Proliferation or Proliferating Cartilage

In this zone, cartilage cells (specifically chondrocytes in lacunae) are undergoing mitosis and are stacking up like coins in line with the long axis of the bone.
• These stacks of cartilage cells that look like coins are isogenous groups.
• These cells are also actively producing matrix.
• With the division oriented in this direction (specifically along the long axis of the bone) and the matrix production - the epiphysis is pushed away from the diaphysis causing the bone to lengthen.


3. Zone of Hypertrophy or Hypertrophic Cartilage

• In this zone, chondrocytes increase in size. In other words, they undergo hypertrophy.
• During this process, the cytoplasm of the chondrocytes accumulates glycogen.
• When the chondrocytes undergo hypertrophy, the matrix is compressed/thinned due to the expansion of the cells.


4. Zone of Calcified Cartilage

• In this zone, the cartilage matrix begins to calcify through the formation of hydroxyapatite crystals. This calcified cartilage matrix stains basophilic.
• Due to the calcified cartilage, the chondrocytes can no longer receive the nutrients they need via diffusion and they die.


5. Zone of Ossification (you may also see this called the Zone of Resorption or Zone of Remodeling)

• This zone is in direct contact with marrow tissue, as it right next to the diaphysis.
• In this zone, small blood vessels, blood cells, osteoprogenitor cells, and osteoclasts enter into the spaces previously occupied by the chondrocytes.
• Bone (specifically primary/woven bone) is laid down by osteoblasts onto the calcified cartilage spicules that were left behind. Remember, bone stains eosinophilic.
• Eventually, much of this new bone and calcified cartilage will be eroded by the osteoclasts, so that secondary bone can be developed or to add space to the already existing medullary cavity.

One thing to keep in mind when it comes to the epiphyseal plate, the epiphyseal plate remains the same width during the growth of an individual:
• This means that cartilage growth must equal bone tissue replacement.
• However, at epiphyseal plate closure - hormones signal for the end of chondrocyte division and bone replaces all of the cartilage. This produces the epiphyseal line.


At Periosteal Surface of Bone

Osteoblasts secrete bone matrix


At Endosteal Surface of Bone

Osteoclasts breakdown bone matrix


Appositional growth

To widen your bones, you will use appositional growth, which means growth along the surface.
To do this, osteoblasts will secrete bone matrix on the external surface of the bone, just below the periosteum. (Remember, there is a deep osteogenic layer associated with the periosteum.)
However, you don’t want to keep adding onto the outer surface of your bone without removing from the inner surface of the bone. Otherwise, your bones will become too thick and, therefore, too heavy for you to move.
Therefore, at the endosteal surface, osteoclasts will resorb or remove bone.
The rate of the activity of the osteoblasts at the periosteal layer should equal the rate of the activity of the osteoclasts at the endosteal layer to keep bones from becoming too heavy or too thin.


Woven vs lamellar in histo

Immature vs mature.


Negative Feedback Loop for Maintenance of Calcium Homeostasis (impacts when remodeling occurs)

Impacts bone remodeling
Parathyroid Hormone

• The controls for remodeling include a negative feedback loop, mechanical stresses, and gravity.
• The negative feedback loop defines WHEN remodeling occurs. This negative feedback loop maintains the homeostasis of a certain amount of Ca2+ in the blood through the release of the hormones calcitonin and parathyroid hormone. Ca2+ is important in the blood as it is needed for many physiological processes.
• The mechanical stresses placed on bones and gravity's pull on bones define WHERE remodeling occurs.


2) Bone’s Response to Mechanical Stress and Gravity (impacts where remodeling occurs)

impacting bone remodeling:


Negative Feedback Loop Maintaining Calcium Homeostasis in the Blood:

• The negative feedback loop defines WHEN remodeling occurs. This negative feedback loop maintains the homeostasis of a certain amount of Ca2+ in the blood through the release of the hormones calcitonin and parathyroid hormone.
• If too much Ca2+is in blood , the parafollicular cells in the thyroid gland secrete calcitonin which inhibits osteoclasts and, therefore, bone resorption, as well as encourages calcium salt to be deposited into bone matrix as it transiently also increases osteoblast activity. These changes lower the elevated blood calcium levels by the removal of Ca2+ from the blood and its deposit into bone.
• If too little Ca2+ is in blood, the parathyroid glands (which are multiple pea-sized glands on the posterior side of the thyroid gland) secrete parathyroid hormone (PTH) which does a number of things including stimulating osteoclasts to resorb bone. This resorption of bone releases Ca2+ from storage in the bone and it enters the blood. This raises low blood calcium levels back to normal levels.