Musculoskeletal system development

Skull

The skull can be divided in two parts: the neurocranium that forms a protective case around the brain, and the viscerocranium that forms the skeleton of the face. The neurocranium itself is divided into two other parts: the membranous part that surrounds the brain as a vault, and the cartilaginous part (chondrocranium) that forms the base of the skull. Both the neurocranium and the viscerocranium have distinct components that are formed either by intramembranous ossification or endochondral ossification.

Neurocranium

The membranous part of the neurocranium forms the calvaria (skullcap). It is derived from two sources: the paraxial mesoderm and the neural crest cells. Mesenchymal cells from these two sources surround the brain at various sites, form primary ossification centers, and undergo intramembranous ossification. This results in the formation of membranous flat bones that are characterized by needle-like bone spicules. Bone spicules progressively radiate from the primary ossification centers toward the periphery. Structures derived from the membranous neurocranium include the parietal bones, part of the temporal bones, and the occipital bone.

At birth, the membranous bones are separated from each other by dense connective tissue membranes that form fibrous joints, known as the cranial sutures (coronal, sagittal, and lambdoid). The site at which more than two bones meet are called the fontanelles (anterior, posterior, and two posterolateral).

• The anterior fontanelle is the most prominent one and is found where the parietal and frontal bones meet.
• The posterior fontanelle is found where the parietal bones and the occipital bone meet.
• The posterolateral (mastoid) fontanelles are found where the parietal, occipital, and temporal bones meet.

As the brain and the skull continue to grow after birth, many of these sutures and fontanelles will remain membranous and open postnatally. Generally, the posterior fontanelle closes first by 2 months of age, the mastoid fontanelle by 6 months, the anterior fontanelle by 18 months, and the cranial sutures by 36 months.

The cartilaginous part of the neurocranium forms the base of the skull. It initially consists of a number of separate cartilages that eventually fuse together. Similar to the membranous neurocranium, the cartilaginous neurocranium is derived from the same sources. The neural crest cells form the prechordal chondrocranium anterior to the center of the sella turcica, whereas the paraxial mesoderm form the chordal chondrocranium posterior to the center of the sella turcica. The development of the base of the skull is complete when these cartilaginous structures fuse and undergo endochondral ossification. Structures derived from the chondrocranium include components of the occipital bone, the sphenoid bone, and the ethmoid bone, specifically the:

• posterior half of the cribriform plate 
• lesser wings of the sphenoid
• greater wings of the sphenoid
• sella turcica
• petrous part of the temporal bones and the adjacent parts of the occipital bone
• clivus 
• condyles of the occipital bone

Viscerocranium

The viscerocranium is mainly formed by the first two pharyngeal arches. The first pharyngeal arch undergoes intramembranous ossification to give rise to the:

• zygoma
• maxilla 
• squamous part of the temporal bone 
• mandible 

The dorsal tip of the mandibular process and the second pharyngeal arch undergo endochondral ossification to give rise to the malleus, the incus, and the stapes. The ossicles are the first bones to become fully ossified, with their ossification beginning in the fourth month of gestation.

Vertebral column

The vertebral column develops from the sclerotomes, the ventromedial part of the somite. By the fourth gestational week , sclerotome cells surround the neural tube and the notochord to merge with cells derived from the opposing somite. Each sclerotome then undergoes resegmentation, a process that involves the caudal half of each sclerotome to fuse with the cranial half of each adjacent sclerotome; this forms the centrum, the primordial vertebral body. Thus, each vertebra develops from two adjacent sclerotomes rather than from one sclerotome.

Not all cells in the caudal half of each sclerotome undergo resegmentation. Instead, some migrate cranially and contribute to the formation of the intervertebral disc. As development continues, the notochord completely degenerates in the centrum, but where it persists, it enlarges as a gelatinous center. This forms the nucleus pulposus, which is later surrounded by circularly arranged fibers known as the annulus fibrosis. Combined, these two structures form the intervertebral discs.

By the sixth gestational week, the sclerotome cells surrounding the neural tube form a cartilaginous vertebral arch, and fuse with the cartilaginous vertebral body. The spinous, transverse, and costal processes develop as extensions from this newly assembled cartilage model. In the lumbar region, the costal processes of the first sacral vertebrae fuse and form the lateral sacral mass, known as the ala of the sacrum. The process of chondrification continues until a cartilaginous vertebral column is fully formed.

Ossification of the vertebrae begins at the seventh gestational week, but only ends during the second decade of adulthood. By the eighth week, three primary ossification centers develop: one at the center of the cartilaginous vertebral body and one on each side of the cartilaginous vertebral arch. At puberty, five secondary ossification centers appear in the vertebrae: one at the tip of the spinous process, one at the tip of each transverse process, and one on both the superior and inferior rim of the vertebral body.

Ribs

Ribs develop from the costal processes of the thoracic vertebrae. They are cartilaginous during the embryonic period and undergo ossification during the fetal period. The original site where the costal process is connected to the vertebra becomes replaced by costovertebral synovial joints. The first seven pairs of ribs attach to the sternum through their own cartilages. The subsequent five pairs of ribs attach to the sternum through the cartilage of the seventh rib. The last two pairs of ribs do not attach to the sternum. Respectively, this forms the true ribs, the false ribs, and the floating ribs.

Sternum

The sternum develops from a pair of separate vertical, condensed bands of mesenchymal cells, known as the sternal bars. These sternal bars form independently lateral to the midline of the ventral body wall. Chondrification occurs while the sternal bars migrate medially. By the tenth gestational week , they fuse in cranial-to-caudal sequence at the midline and form the cartilage model of the manubrium, the sternal body, and the xiphoid process.

Limbs

The appendicular skeleton includes the bones of the limbs and girdles. The formation of these structures begin by the end of the fourth gestational week, where limb buds become visible as outpocketings from the ventrolateral body wall. They consist of a core of mesenchymal cells - derived from the somatic layer of the lateral plate mesoderm - covered by a layer of ectoderm. At the distal border of the limb, the ectoderm forms the apical ectodermal ridge (AER). The AER exerts an inductive influence on the core of mesenchymal cells to remain undifferentiated and to rapidly proliferate; this region is known as the progress zone. As the limbs continue to grow, cells farther from the influence of the AER begin to differentiate into cartilage and muscle. Development of the limbs thus proceed proximodistally.

By the sixth gestational week, a circular constriction separates the terminal and proximal portions of the limb buds. Later, a second circular constriction separates the proximal portion into two additional segments; the familiar parts of the limbs thus become recognizable. Meanwhile, the terminal portion becomes flattened to form the handplates and footplates. Further formation of fingers and toes depends on three factors: their continued outgrowth under the influence of the AER, mesenchymal condensation to form cartilaginous digital rays, and apoptosis of intervening tissue between the rays. Cell death in the AER creates separate ridges for each digit forming webbed fingers and toes. Further cell death in the interdigital spaces are what creates the separation of the digits. By the end of the eight week, digit separation is complete while the fingers develop distal swellings known as tactile pads, which are what create patterns for fingerprints.

The structural development of the upper limbs and lower limbs are similar but with two exceptions: the development of the lower limb is approximately 1 to 2 days behind that of the upper limb, whereas the upper and lower limbs rotate in opposite directions. By the seventh gestational week, the upper limbs rotate 90° laterally, placing the extensor muscles on the lateral and posterior surface and the thumb laterally. On the other hand, the lower limbs rotate 90° medially, placing the extensor muscles on the anterior surface and the big toe medially.

Appendicular skeleton

While the external shape of the limbs becomes established, the bones of the limbs and girdles (with the exception of the clavicle) form by a two-step process: chondrification and endochondral ossification. In contrast, the clavicle is a membrane bone: it forms directly by intramembranous ossification. Chondrification involves the condensation and differentiation of mesenchymal cells into chondrocytes (cartilage cells). By the sixth gestational week, these chondrocytes differentiate into hyaline cartilage models, foreshadowing the prospective bones. While the process of forming these cartilage models is initiated, synovial joints form between the two chondrifying bone primordia at the interzone.

At the center of the cartilage model (diaphysis), primary ossification centers form where chondrocytes increase in size, calcify the matrix, and eventually die. Concurrently, blood vessels invade the diaphysis. This results in the recruitment of osteoblasts, the differentiation of certain invading cells into hematopoietic cells (blood cells of the bone marrow), and the restriction of proliferating chondrocytes towards the distal ends of the cartilage model (epiphyses). Endochondral ossification thus begins from these primary ossification centers at the diaphysis and proceeds toward the epiphyses. However, this process only starts by the end of the embryonic period.

At birth, the diaphysis of long bones is usually completely ossified, whereas the epiphyses are still cartilaginous. Only after birth, secondary ossification centers develop in the epiphyses, which will also undergo the same ossification and vascularization processes that took place in the diaphysis. However, a layer of epiphyseal cartilage plate, known as the growth plate, persists between the epiphyses and the diaphysis. Continued proliferation of the chondrocytes in the growth plate is what allows the diaphysis to lengthen and thus what maintains the growth of bones. Only at approximately 20 years of age are when the epiphyses and diaphysis fuse, indicating that skeletal growth is complete.