Endochondral ossification[1][2] is one of the two essential pathways by whichbone tissue is produced duringfetal development of themammalianskeletal system, the other pathway beingintramembranous ossification. Both endochondral and intramembranous processes initiate from a precursormesenchymal tissue, but their transformations into bone are different. In intramembranous ossification, mesenchymal tissue is directly converted into bone. On the other hand, endochondral ossification starts with mesenchymal tissue turning into an intermediatecartilage stage, which is eventually substituted by bone.[3]
The initiation of endochondral ossification starts by proliferation and condensation ofmesenchymal cells in the area where the bone will eventually be formed. Subsequently, these mesenchymal progenitor cells differentiate intochondroblasts, which actively synthesize cartilage matrix components. Thus, the initial hyaline cartilage template is formed, which has the same basic shape and outline as the future bone.[8]
This hyaline cartilage template expands through both:[8][9]
Interstitial growth
Appositional growth
Cellular protagonists
Chondrocytes present within the existing cartilage.
A schematic forlong bone endochondral ossification.
In developing bones, ossification commences within the primary ossification center located in the center of thediaphysis (bone shaft),[5] where the following changes occur:
The perichondrium surrounding the cartilage model transforms into theperiosteum. During this transformation, special cells within the perichondrium switch gears. Instead of becoming cartilage cells (chondrocytes), they mature into bone-buildingosteoblasts.[5] This newly formed bone can be called "periosteal bone" as it originates from the transformed periosteum. However, considering its developmental pathway, it could be classified as "intramembranous bone".[8]
After the formation of the periosteum, chondrocytes in the primary center of ossification begin to grow (hypertrophy). They begin secreting:[10][11]
Alkaline phosphatase, which causes calcification of the cartilage matrix. This calcification prevents passage of nutrients to chondrocytes leading to their death.
When chondrocytes die, matrix metalloproteinases result in catabolism of various components within the extracellular matrix and the physical boundaries between neighboringlacunae (the spaces housing chondrocytes) weaken. This can lead to the merging of these lacunae, creating larger empty spaces.[8][9]
Blood vessels arising from the periosteum invade these empty spaces and mesenchymal stem cells migrate guided by penetrating blood vessels. Following the invading blood vessels, mesenchymal stem cells reach these empty spaces and undergo differentiation into osteoprogenitor cells. These progenitors further mature into osteoblasts, that deposit unmineralized bone matrix, termed osteoid. Mineralization subsequently follows leading to formation of bone trabeculae (Endochondral bone formation).[11]
During the postnatal life, a secondary ossification center appears in each end (epiphysis) of long bones. In these secondary centers, cartilage is converted to bone similarly to that occurring in a primary ossification center.[8] As the secondary ossification centers enlarge, residual cartilage persists in two distinct locations:[11]
Articular cartilage: This layer coats the bone ends, concerned withjoint movement.
Epiphyseal growth plate: This transverse layer lies between theepiphysis anddiaphysis. It’s composed of highly active chondrocytes and responsible for longitudinal bone growth. Consequently, the bone elongates at this growth plate until closure occurs at skeletal maturity.
At the end of an individual’s growth period, the production of new cartilage in the epiphyseal plate stops. After this point, existing cartilage within the plate turns into mature bone tissue.[8]
In this zone,chondrocytes are either dying or dead, leaving cavities that will later become invaded by bone-forming cells. Chondrocytes here die when they can no longer receive nutrients or eliminate wastes via diffusion. This is because the calcified matrix is much less hydrated than hyaline cartilage.
Zone of ossification
Osteoprogenitor cells invade the area and differentiate into osteoblasts, which elaborate matrix that becomes calcified on the surface of calcified cartilage.
For complete recovery of afractured bone’s biomechanical functionality, thebone healing process needs to culminate in the formation of lamellar bone at the fracture site to withstand the same forces and stresses it did before the fracture.Indirect fracture healing, the most common type of bone repair,[10] relies heavily on endochondral ossification. In this type of healing, endochondral ossification occurs within the fracture gap and external to the periosteum. In contrast, intramembranous ossification takes place directly beneath the periosteum, adjacent to the broken bone’s ends.[10][12]
A schematic of endochondral fracture, whereB shows the location of both endochondral and intramembranous ossification.
Masson Goldner trichrome stain of growth plate in a rabbit tibia.
Section of fetal bone of cat. ir. Irruption of the subperiosteal tissue. p. Fibrous layer of the periosteum. o. Layer of osteoblasts. im. Subperiosteal bony deposit.
Process of endochondral ossification.
Drawing of part of a longitudinal section of the developing femur of a rabbit. a. Flattened cartilage cells. b. Enlarged cartilage cells. c, d. Newly formed bone. e. Osteoblasts. f. Giant cells or osteoclasts. g, h. Shrunken cartilage cells.
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