OSTEOGENESIS

(Bone development or ossification)

Bone can develop either directly from an initial cell condensation of the mesenchyme (intramembranous ossification) or by gradual replacement of a pre-existing tissue, the cartilage, which acts as a template (endochondral ossification; bone formation inside cartilage).

The initial mechanism of bone formation during intramembranous and endochondral ossification is essentially the same:

An initial trabecular network, called primary spongiosa, is first laid down and then transformed into mature bone .

Intramembranous ossification ( 5-1 and 5-2 )

Intramembranous ossification of certain parts of the skull and the clavicle occurs in the following sequence (see 5-1 ):

  • 1.

    The embryonic connective tissue (mesenchyme) becomes highly vascularized and mesenchymal stem cells aggregate while still embedded in an extracellular matrix containing collagen fibers and proteoglycans.

  • 2.

    Aggregated mesenchymal stem cells directly differentiate into osteoblasts that begin to secrete osteoid or bone matrix . Osteoid is the unmineralized , organic portion of the bone matrix.

    Numerous osteogenesis centers develop and eventually fuse, forming a network of anastomosing trabeculae resembling a sponge, the so-called spongy bone or primary spongiosa .

  • 3.

    Because collagen fibers in the newly formed trabeculae are randomly oriented, the early intramembranous bone is described as woven bone , in contrast with the regularly oriented collagen fibers of the lamellar or compact bone formed later during bone remodeling.

  • 4.

    Calcium phosphate is deposited in the bone matrix or osteoid, which becomes mineralized . Osteoid is laid down by apposition . No interstitial bone growth occurs.

  • 5.

    Bone matrix mineralization leads to two new developments (see 5-2 ): the entrapment of osteoblasts as osteocytes within the mineralized bone matrix that is remodeled by the bone resorptive osteoclasts and the partial closing of the perivascular channels, which assume the new role of blood formation by conversion of mesenchymal stem cells into blood-forming cells.

5-1, Intramembranous ossification

5-2, Intramembranous ossification

Osteocytes remain connected to each other by cytoplasmic processes enclosed within narrow tunnels called canaliculi . New osteoblasts are generated from preosteoblasts, the osteoprogenitor cells, located adjacent to the blood vessels.

The final developmental includes these steps:

  • 1.

    The conversion of woven bone to lamellar (compact) bone . In lamellar bone, the newly synthesized collagen fibers are aligned into bundles with a regular orientation. Lamellae, arranged in concentric rings around a central haversian canal occupied by a blood vessel, form osteons , or haversian systems . Membranous bones remain as spongy bone in the center, the diploë , enclosed by an outer and an inner layer of lamellar compact bone.

  • 2.

    The condensation of the external and internal connective tissue layers to form the periosteum and endosteum , respectively, containing osteoprogenitor cells.

At birth, bone development is not complete and the bones of the skull are separated by spaces ( fontanelles) housing osteogenic tissue. The bones of a young child contain woven and lamellar bony matrix.

Endochondral ossification ( 5-3 to 5-10 )

Endochondral ossification is the process by which skeletal cartilage templates are replaced by bone. Bones of the extremities, vertebral column and pelvis (the appendicular skeleton) derive from a hyaline cartilage template.

5-3, Endochondral ossification: Primary center of ossification

5-4, Endochondral ossification: Secondary centers of ossification

5-5, Endochondral ossification: Zones of bone development

5-6, Endochondral ossification: Zones of bone development

5-7, Endochondral ossification: Proliferative and hypetrophic zones

5-8, Endochondral ossification: Vascular invasion zone

5-9, Growth in length of the diaphysis

5-10, Ihh, epiphyseal growth plates and bone growth in length

As in intramembranous ossification, a primary bone development center is formed during endochondral ossification (see 5-3 ). Unlike intramembranous ossification, this center of bone development starts when proliferated chondrocytes deposit an extracellular matrix containing type II collagen.

Shortly thereafter, chondrocytes in the central region of the cartilage undergo hypertrophy and synthesize type X collagen , a marker for hypertrophic chondrocytes.

Angiogenic factors secreted by hypertrophic chondrocytes (vascular endothelial cell growth factor, VEGF) induce the invasion of blood vessels from the perichondrium to form a nascent bone marrow cavity.

These events result in the formation of the primary bone development center . Hypertrophic chondrocytes undergo apoptosis as calcification of the matrix in the middle of the shaft of the cartilage template takes place.

At the same time, the inner perichondrial cells exhibit their initial bone development potential and a thin periosteal collar of bone is formed around the midpoint of the shaft, the diaphysis . Consequently, the primary bone development center ends up located inside a cylinder of bone. The periosteal collar, formed under the periosteum by apposition, consists of woven bone. The periosteal collar is later converted into compact bone.

The following sequence of events defines the next steps of endochondral ossification (see 5-4 ):

  • 1.

    Blood vessels invade the space formerly occupied by the hypertrophic chondrocytes and they branch and project toward either end of the center of bone development. Blind capillary ends extend into spaces formed within the calcified cartilage.

  • 2.

    Osteoprogenitor cells (preosteoblasts) and blood development stem cells reach the core of the calcified cartilage through the perivascular connective tissue surrounding the invading blood vessels. Then, preosteoblasts differentiate into osteoblasts that aggregate on the surfaces of the calcified cartilage and begin to deposit bone matrix (osteoid) .

  • 3.

    At this developmental step, a primary center of ossification, defined by the periosteal collar and the center of ossification in the interior of the cartilage template, is organized at the diaphysis .

Secondary centers of ossification develop later in the epiphyses .

The growth in length of the long bones depends on the growth in length of the hyaline cartilage, while the center of the cartilage is being replaced by bone at the equidistant zones of ossification.

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