Figure 813

Section of mandible developing by the process of intramembranous ossification. This photomicrograph shows a section from a developing mandible, stained with H8E. In this relatively early stage of development, the mandible consists of bone spicules of various sizes and shapes. The bone spicules interconnect with each other and form trabeculae, providing the general shape of the developing bone (no cartilage model is present). The numerous osteoblasts responsible for this growing region of spicules are seen at the surface of the newly deposited bone. The older, calcified portion of spicules contains osteocytes surrounded by bone matrix. In the right portion of the figure, adjacent to the bone spicules, the connective tissue is very cellular and is developing into the early periosteum. x250.

Newly formed bone matrix appears in histologic sections as small, irregularly shaped spicules and trabeculae

With time, the matrix becomes calcified, and the interconnecting cytoplasmic processes of the bone-forming cells, now termed osteocytes, are contained within canali-culi. Concomitantly, more of the surrounding mesenchymal cells in the membrane proliferate, giving rise to a population of osteoprogenitor cells. Some of the osteo-progenitor cells come into apposition with the initially formed spicules, become osteoblasts, and add more matrix. By this process, called appositional growth, the spicules enlarge and become joined in a trabecular network with the general shape of the developing bone.

1 94 CHAPTER 8 ! Bone

Through continued mitotic activity, the osteoprogenitor cells maintain their numbers and thus provide a constant source of osteoblasts for growth of the bone spicules. The new osteoblasts, in turn, lay down bone matrix in successive layers, giving rise to woven bone. This immature bone, discussed on page 185, is characterized internally by interconnecting spaces occupied by connective tissue and blood vessels. Bone tissue formed by the process just described is referred to as membrane bone or intramembranous bone.

Endochondral Ossification

Endochondral ossification also begins with the proliferation and aggregation of mesenchymal cells at the site of the future bone. However, the mesenchymal cells differentiate into chondroblasts that, in turn, produce cartilage matrix.

Initially, a hyaline cartilage model with the general shape of the bone is formed

Once established, the cartilage model (a miniature version of the future definitive bone) grows by interstitial and appositional growth. The increase in the length of the cartilage model is attributed to interstitial growth. The increase in its width is largely due to the addition of cartilage matrix produced by new chondrocytes that differentiate from the chondrogenic layer of the perichondrium surrounding the cartilage mass. Illustrations 1 and 1 a of Figure 8.14 show an early cartilage model.

The first sign of ossification is the appearance of a cuff of bone around the cartilage model

At this stage, the perichondria! cells in the midregion of the cartilage model no longer give rise to chondrocytes. Instead, bone-forming cells or osteoblasts are produced. Thus, the connective tissue surrounding this portion of the cartilage is no longer functionally a perichondrium; rather, because of its altered role, it is now called periosteum. Moreover, because the cells within this layer are differentiating into osteoblasts, an osteogenic layer can now be identified within the periosteum. As a result of these changes, a layer of bone is formed around the cartilage model. This bone can be classified as either periosteal bone, because of its location, or intramembranous bone, because of its method of development. In the case of a long bone, a distinctive cuff of periosteal bone, the bony collar, is established around the cartilage model in the diaphyseal portion of the developing bone. The bony collar is shown in illustrations 2 and 2a of Figure 8.14.

With the establishment of the periosteal bony collar, the chondrocytes in the midregion of the cartilage model become hypertrophic

As the chondrocytes enlarge, their surrounding cartilage matrix is resorbed, forming thin irregular cartilage plates between the hypertrophic cells. The hypertrophic cells begin to synthesize alkaline phosphatase, and concomitantly, the surrounding cartilage matrix undergoes calcification (see illustrations 3 and 3a of Fig. 8.14). The calcification of the cartilage matrix should not be confused with calcification that occurs in bone tissue.

The calcified cartilage matrix inhibits diffusion of nutrients, causing death of the chondrocytes in the cartilage model

With the death of the chondrocytes, much of the matrix breaks down, and neighboring lacunae become confluent, producing an increasingly large cavity. While these events are occurring, one or several blood vessels grow through the thin diaphyseal bony collar to vascularize the cavity (see illustrations 4 and 4a of Fig. 8.14).

Periosteal cells migrate into the cavity along with growing blood vessels

Cells from the periosteum migrate with the penetrating blood vessels and some of the primitive periosteal cells to become osteoprogenitor cells in the cavity. Other primitive cells also gain access to the cavity via the new vasculature, leaving the circulation to give rise to the marrow. As the calcified cartilage breaks down and is partially removed, some remains as irregular spicules. When the osteoprogenitor cells come in apposition to the remaining calcified cartilage spicules, they become osteoblasts and begin to lay down bone (osteoid) on the spicule framework. Thus, the bone formed in this manner may be described as endochondral bone. The combination of bone, which is initially only a thin layer, and the underlying calcified cartilage is described as a mixed spicule.

Histologically, mixed spicules can be recognized by their staining characteristics. Calcified cartilage tends to be basophilic, whereas bone is distinctly eosinophilic. With the Mallory stain, bone stains a deep blue, and calcified cartilage stains light blue (Fig. 8.15). Also, calcified cartilage no longer contains cells, whereas the newly produced bone may reveal osteocytes in the bone matrix. Such spicules persist for a short time before the calcified cartilage component is removed. The remaining bone component of the spicule may continue to grow by appositional growth, thus becoming larger and stronger, or it may undergo resorption as new spicules are formed.

Growth of Endochondral Bone

Endochondral bone growth begins in the second trimester of fetal life and continues into early adulthood

The events described above represent the early stage of endochondral bone formation as seen in the fetus, beginning at about the 12th week of gestation. The continuing growth process, which takes place throughout the growth

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