Development of the Musculoskeletal System
Musculoskeletal anatomy is fascinating since it gives us insights as to how our body utilizes our muscles, bones, and joints to give us the ability to navigate in the world. If this article peaks your interest, you probably have a solid foundation in this topic and are ready to take your knowledge to the next level. By studying the embryological development of the musculoskeletal system, you will achieve a better understanding of how different types of congenital anomalies can occur.
The musculoskeletal system develops from three sources:
- the paraxial mesoderm
- the parietal layer of the lateral plate mesoderm
- the neural crest cells
The development of bone and muscle begins at the fourth gestational week, when the paraxial mesoderm differentiates into somites; the latter gives rise to sclerotomes and dermomyotomes. Sclerotomes form the vertebra and the ribs, whereas myotomes form the majority of the muscular system.
Bone formation can occur either by intramembranous ossification or endochondral ossification. Although different, the occurrence of both processes first require the condensation of mesenchymal cells - the loosely organized embryonic connective tissue. Intramembranous ossification underlies the formation of the cranial vault, many bones of the face, and the clavicle. Endochondral ossification underlies the formation of the base of the skull, some bones of the face, the bones of the limbs and girdles, the vertebral column, the ribs, and the sternum.
Development of the limbs involves the inductive influences of the apical ectodermal ridge, the formation of circular constrictions to separate parts of the limbs, and opposite rotations of the upper and lower limbs. Development of the skeletal muscle involves the differentiation of myotome cells into myoblasts. This article will discuss the embryological development of the axial skeleton, the appendicular skeleton, and the skeletal muscle, as well as the associated malformations that may occur.
Development of Bone
The first stage of any type of bone formation involves a mesenchymal condensation, where cells become densely packed together. From this point on, there are two ways osteogenesis can occur: intramembranous ossification and endochondral ossification. The process in which mesenchymal cells ensheathed in membranous tissue directly undergo ossification is known as intramembranous ossification. The process in which mesenchymal cells first differentiate into cartilage models before undergoing ossification is known as endochondral ossification.
Formation of the cranial vault, most bones of the face, and the clavicle occur by intramembranous ossification, whereas formation of the rest of the axial and appendicular skeleton occur by endochondral ossification. In other words, the base of the skull, some bones of the face, the vertebral column, the ribs, the sternum, and the bones of the limbs and girdles form by a two-step process: chondrification and ossification.
Development of Joints
During the sixth gestational week, joints begin to develop with the formation of condensed mesenchyme in the interzone, the region between two bone primordia. Joints are classified as:
The development of fibrous joints involves mesenchymal cells in the interzone to differentiate into dense fibrous tissue (i.e. sutures of the skull). The development of cartilaginous joints involves mesenchymal cells in the interzone to differentiate into hyaline cartilage (i.e. costochondral joints) or fibrocartilage (i.e. pubic symphysis). The development of synovial joints involves a more extensive process: the central mesenchymal cells in the interzone undergo apoptosis to form the synovial joint cavities, whereas the peripheral cells differentiate into ligaments and dense fibrous tissue. Sequentially, the dense fibrous tissue forms the articular cartilage that covers the ends of the adjacent bone primordia. The remaining mesenchymal cells surrounding the interzone differentiate into chondrocytes to form the joint capsules and the synovial membrane.
Development of Axial Skeleton
The axial skeleton includes the:
- vertebral column
The skull consists of a neurocranium and a viscerocranium, with each having membranous and cartilaginous components. The bones that make up the skull thus form either by intramembranous ossification or endochondral ossification. The bones that make up the vertebral column, the ribs, and sternum form only by endochondral ossification. The vertebral column develops from a resegmentation process of the somites, while the ribs develop as extensions from the thoracic vertebrae. The sternum develops as two independent bands of mesenchymal cells before fusing and ossifying as one.
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.
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
- condyles of the occipital bone
The viscerocranium is mainly formed by the first two pharyngeal arches. The first pharyngeal arch undergoes intramembranous ossification to give rise to the:
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.
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 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.
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.
Development of Limbs and Appendicular System
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.
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.
Development of Skeletal Muscle
Skeletal muscle is derived from the mesoderm. Recall that the paraxial mesoderm forms segmented series of tissue blocks on each side of the neural tube, the somites. Cells in the ventromedial part of the somite form the sclerotome. Cells in the dorsal part form the dermatome and two edges, the ventrolateral lip and the dorsomedial lip. Cells from these two edges migrate ventral to the dermatome and proliferate to form muscle cell precursors. Collectively, these structures form the dermomyotome. In turn, the dermomyotome will differentiate into dermatome cells forming the dermis of the back and the neck, and myotome cells forming the skeletal muscles.
Before developing into skeletal muscles, myotome cells first differentiate into myoblasts (embryonic muscle cells) through elongation of their nuclei and cell bodies. Myoblasts fuse to form elongated, multinucleated, and cylindrical muscle fibers. During or after fusion, myofilaments and myofibrils develop in the cytoplasm. As development continues, the muscle cells become invested with the external laminae, segregating them from the surrounding connective tissue. Fibroblasts form the epimysium and perimysium layers of the muscle, whereas the external lamina and reticular fibers form the endomysium. In limbs, myoblasts migrate to the limb buds and surround the primordial limb bones. The pattern of muscle formation is dictated by the same mesenchymal cells that give rise to the bones.
Malformations of the skull include cranioschisis and craniosynostosis. Cranioschisis involves the failure of the cranial vault to form, thus exposing the brain tissue to amniotic fluid, resulting in anencephaly. Craniosynostosis involves the premature closure of one or more sutures of the skull. Premature closure of the sagittal suture can result in a long and narrow skull due to frontal and occipital expansions. Premature closure of the coronal suture can result in a short skull. As such, premature unilateral closure of sutures can result in an asymmetrical skull.
Malformations of the vertebra include Klippel-Feil sequence and spina bifida. Klippel-Feil syndrome involves the fusion of cervical vertebrae, which results in reduced mobility, short neck, and low hairline. Spina bifida involves the failure of vertebral arches to fuse, thus generally exposing the spinal cord in the sacral region. In spina bifida occulta, there are minimal neurological deficits; the spinal cord is intact and is covered by skin. In spina bifida cystica, the meninges and/or the neural tissue protrude through the skin at the sacral region to form a cyst-like sac.
Malformations of the ribs include accessory ribs and fused ribs. Accessory ribs are usually rudimentary and unilateral or bilateral; they develop from the costal processes of cervical or lumbar vertebrae. Cervical ribs are usually attached to the seventh cervical vertebrae. Lumbar ribs are usually clinically insignificant, whereas cervical ribs may impinge on the brachial plexus or subclavian vessels, resulting in varying degrees of anesthesia of the upper limbs. Fused ribs occur posteriorly when two or more ribs arise from a single vertebra.
Malformations of the sternum include cleft sternum, pectus excavatum, and pectus carinatum. Cleft sternum is the result of a complete or partial midline fusion of the sternal bars. The heart and its major vessels are covered only by skin and soft tissue and thus are unprotected. Pectus excavatum (hollow chest) involves a concave depression of the sternum. Pectus carinatum (keel-shaped chest) involves an anterior projecting sternum. Both congenital deformities are often asymptomatic, but may impair cardiac and respiratory function depending on the severity.
Malformations of the limbs vary greatly and can include defects in the entirety of the limb, the hand or the foot, and the digits. Malformation of the entire limbs include amelia, meromelia, phocomelia, and micromelia. Amelia (no limb) involves the complete absence of one or more limbs, whereas meromelia (part limb) involves a partial absence. Phocomelia (seal limb) involves the absence of long bones, resulting in rudimentary hands and feet attached to the trunk and pelvis. Micromelia involves abnormally small limbs.
Malformation of the hands and feet is known as cleft hand and cleft foot, which consist of an abnormal cleft between the second and fourth metacarpal or metatarsal bones and soft tissues. The third phalangeal and metacarpal or metatarsal bones are almost always absent, resulting in the possible fusion of the adjacent digits.
Malformations of digits include brachydactyly, syndactyly, polydactyly, and ectrodactyly. Brachydactyly involves shortened digits. Syndactyly involves the fusion of two or more digits. Polydactyly involves the presence of extra digits. Ectrodactyly involves the absence of a digit.
Skeletal Muscle Malformations
Malformations of skeletal muscle can result in certain conditions such as Poland sequence, prune belly syndrome and muscular dystrophy. Poland sequence involves the absence of the pectoralis minor, partial absence of the pectoralis major, the absence or displacement of the nipple and areola, and the accompanying presence of digital defects. Prune belly syndrome involves the partial or complete absence of abdominal muscles; this results with a very thin abdominal wall, making the internal organs visible and easy to palpate. Muscular dystrophy involves a group of inherited muscle diseases that cause progressive muscular atrophy and weakness.