Musculoskeletal Development

The musculoskeletal system provides movement, support, protection, and stability to the body and its organs. Development of the musculoskeletal system is a complex process that involves cellular differentiation and the formation and development of bones, muscles, and connective tissues from the somites and other parts of the mesoderm. Muscle development is called myogenesis, cartilage development is called chondrogenesis, whereas bone development is known as osteogenesis and occurs by two methods which are intramembranous ossification and endochondral ossification. The bone muscle and cartilage development continue postnatally throughout childhood and adolescence.

Embryonic development of the musculoskeletal system commences in the early stages of the embryonic development at about the 4^th week of gestation. Its first indication is the differentiation of the mesoderm into paraxial, intermediate, and lateral mesoderm following by differentiation of the paraxial mesoderm into somites. The process of development and differentiation of somites is called somitogenesis, which involves the appearance of paired cellular masses flanking the axial mesoderm or notochord.

Fig. 12.1. Two illustrations showing the location of the somites in developing embryos in the  early stages of their development. The illustration on the right is a dorsal view of a wholemount embryo at the 8-somites stage; eight pairs of somites are flanking the longitudinal axis of the embryo’ on either side of the neural groove / tube, whereas the illustration on the left shows the cross-sectional appearance of a developing embryo. The somites are flanking the notochord (the axial mesoderm). Lateral to the somites is the intermediate mesoderm and further lateral is the lateral mesoderm (somatic and splanchnic plates).

The Somites

Within the paraxial mesoderm cells of the mesodermal organize themselves into bands or whorls called the somatomeres, which represent an early stage of the body’s segmentation. The mesodermal cells gradually organize themselves into discrete units known as the somites. Each somite is enclosed by an epithelial layer that establishes a boundary between mesodermal cells of the somite and other surrounding cells. Somatic mesodermal cells gradually form distinct compartment, each compartment representing a separate lineage. These compartments are dermatomes, the sclerotomes, the syndetomes and the myotomes. The most important features of somitogenesis are periodicity, epithelialization, specification, and differentiation. The hairy gene apparently controls the periodicity. Fibronectin and N-cadherin stimulate epithelialization and transformation of somite mesenchymal cells into epithelial masses. Although somites look similar, but they have axial specification; thus, somites of the thoracic region can differentiate into ribs whereas somites of the neck and lumbar regions cannot differentiate into ribs. Somatic cells are to begin with multipotent cells that differentiate along lines forming four distinct areas each committed to differentiate into specific tissues; these areas are the dermatomes, sclerotomes, myotomes and sydesmotomes.

Fig. 12.2.  The illustration shows the differentiation of the somite into dermatome, myotome, syndetomes and sclerotome.

The first somites appear in the anterior portion of the trunk, and new somites are formed rostral to the existing ones at regular intervals. Although somites are transient structures, they are very important in organizing the segmental pattern of the human embryo. Moreover, the somites determine the migration paths of neural crest cells and spinal nerve fibers.

The Dermatomes

Dermatome is the dorsolateral region of the somite which is responsible for forming the connective tissue of dermis of the skin, particularly that of the dermis of the back skin. It gives rise to dermis which is the connective tissue layer that underlies the epidermis, the latter being epithelial in nature. The dermis provides anchorage, blood supply and nerve supply to the epidermis. The dermis has two layers, the papillary dermis which is superficial and is made of a loose connective tissue, and the reticular layer which lies deeper to the papillary layer and is made of dense irregular connective tissue. The dermis overlies the hypodermis or subcutis. In adults the dermatome is an area of the skin that is supplied by afferent nerve fibers originating from a single dorsal root ganglion. This is because somites develop near the developing neural tube and the developing spinal ganglia. Nerve fibers from each spinal ganglion supply the adjacent somite and its dermatome. Cells from the dermatome migrate away to form the dermis of skin in wide areas. They migrate along with the associated nerve fibers. This causes segmentation of the skin of the entire body into dermatomes on the basis of the somite they originate from. This means that  each dermatome corresponds to a segment of the spinal cord. Sensory information from these areas is transmitted via sensory nerve fibers to their respective spinal segment.

Fig. 12.3. The illustrations show segmentation of the skin into dermatomes in an anterior view (left) and a posterior view (right).

There are 31 spinal cord segments in the body; each of these segments has a pair nerve roots on each side of the spinal cord, right and left.  Moreover, on each side there is a ventral or anterior root and dorsal or posterior nerve root.  The ventral root is motor whereas the dorsal one is sensory.  The anterior (ventral) and posterior (dorsal) roots join together on each side to form a spinal nerve that exits the vertebral canal through the intervertebral foramen.

Fig. 12.4. The illustration shows the dorsal and ventral roots of the spinal nerve, and the spinal ganglion which is associated with the dorsal root.

The 31 spinal segments give rise to 31 pairs of spinal nerves, which are distributes as follows, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal spinal nerve. A dermatomes exists for each of these spinal nerves, except the first cervical spinal nerve which is primarily motor. The sensory input from any one of these dermatome is transmitted by the sensory nerve fibers via the spinal nerve of a specific segment of the spinal cord to the corresponding sensory spinal ganglion. Thus, a dermatome is a specified area of the skin innervated by sensory fibers of single dorsal nerve root.  

Fig. 12.5. The illustration on the left shows the endings of nerve fibers of the dorsal spinal root are sensory, whereas the illustration of the left shows the contours of the dermatomes supplied by the dorsal root of C3, C4, C5, T2, T3, T4, T5, T6, T7 and T8 in a front view. Dermatomes on the right are supplied by sensory fibers of the left posterior root ganglia are shown in yellow colour, whereas dermatomes on the left are supplied by sensory fibers of the right posterior root ganglia are shown in green colour.

The sclerotomes

Sclerotomes are transient embryonic structures that contribute to formation of the axial skeleton; they give rise to the vertebrae and ribs, and associated ligaments. They are derived from the ventromedial parts of somites. Sclerotomes are subdivided into different compartments that give rise to specific parts of the axial skeleton. The sclerotome differentiates into different compartments, referred to as the ventral compartment, the lateral compartment, the dorsal compartment, and the central compartment. Sclerotome differentiation requires transformation of the compact mass of epithelial cells into a loose mesenchyme and then detachment from the somites. Several biomolecules are involved in the process of differentiation of the sclerotome, which include Bapx-1, Pax-1 and Pax-9. The thus induced sclerotome cells migrate towards the neural tube, to occupy a position ventral to the neural tube engulfing the notochord. There they  begin to develop into various parts of the vertebrae. The ventral compartment of the sclerotome develops into the vertebral bodies (the centrums) and of part of the intervertebral discs. The dorsal compartment of the sclerotome grows dorsally and enclose the lateral and dorsal aspects of the neural tube, thus forming the neural arches and the spinous process of vertebra. Differentiation compartment of the sclerotome is stimulated by Msx-1, Msx-2, and Xic-1.   

The vertebra develops by a process known as endochondral ossification. The mesenchymal cells of the sclerotome differentiate in chondroblasts and lay down the cartilage matrix form hyaline cartilage; thus, a cartilaginous mode the vertebra is formed. Within the cartilaginous model primary and secondary ossification centers develop. The primary ossification center develops in the vertebral body region in the 9^th week of gestation and continues to the 3^rd trimester. Calcium deposit in the hyaline cartilage causes degeneration of the cartilage. Blood vessels invade the degenerating cartilage bringing in osteoprogenitor cells which differentiate into osteoblasts that lay done the bone matrix. Later on, secondary ossification centers appear in a similar manner but at different locations resulting in the formation of the vertebral arches and processes. In this way the body vertebrae are formed consisting of body, arches and processes. Ossification first takes place in the cervical vertebrae, then the thoracic and progress down the spinal column.

The vertebral body, which is also known as the centrum, is the thick, anterior (ventral) part of the vertebra that bears most of the weight and stress placed on the spine. The neural arch is the posterior portion of the vertebra; it consists of the pedicles and laminae which form the vertebral foramen through which the spinal cord passes. The processes are bony projections that emerge from the vertebra, and serve as attachment points for ligaments and tendons, and also provide articulation between neighboring vertebrae.

Fig. 12.6.  The illustration on the left shows parts of a developing vertebra, whereas the one on the right shows parts of a mature vertebra.

The intervertebral Discs

Development of intervertebral discs begins during mid-embryogenesis when the notochord, a transient structure, becomes segmented and forms the nucleus pulposus, the central core of the disc and the annulus fibrosus, the outer fibrous ring of the disc that surrounds the nucleus pulposus.

Notochord's Role:

The notochord develops in the very stages of embryonic development representing the axial mesoderm which is located beneath the neural tube. During development of the vertebral column, the developing vertebral bodies engulf the notochord. The notochord disappears in those regions where the vertebral body develops but remains in those regions between adjacent vertebral bodies where they expand and develop forming the nucleus pulposus of the intervertebral discs. The annulus fibrosus of the intervertebral discs develops from the surrounding mesenchyme forming a dense connective tissue sheath that surrounds the nucleus pulposus. Some of the mesenchymal cells differentiate into chondroblasts that lay down flakes of hyaline cartilage thus transforming the connective tissue of the annulus fibrosus into fibrocartilage. This fibrocartilaginous ring constitutes a tough investment that surrounds the annulus fibrosus. The inner parts of the annulus fibrosus is made up of type-2 collagen fibers, whereas the outer layer of the annulus fibrosus is made type-1 collagen fibers. The development of the vertebrae and the intervertebral discs is coordinated by various signaling factors, including the hedgehog factor, bone morphogenetic proteins (BMPs), and the transforming growth factor-beta (TGF-β).

Fig. 12.7. The illustration of the left shows two adjacent vertebra and the intervertebral disc in between in a lateral view; only the annulus fibrosus of the intervertebral disc is visible. The illustration on the right shows the process of development of the intervertebral disc from the notochord (nucleus pulposus) and the sclerotome (the annulus fibrosus).

Development of the Ribs

The ribs are of mesodermal origin, namely from the paraxial mesoderm and specifically from the sclerotome of somites. To begin with, some cells of the sclerotome differentiate into chondrogenic cells that lay hyaline cartilage models of the ribs that project from the costal processes of the developing thoracic vertebrae. These models elongate and take the shape of the ribs, whether true ribs, false ribs and false ribs. True ribs have direct attachment to the sternum, false ribs have indirect attachment to the sternum via cartilage, whereas floating ribs have no attachment to the sternum.

Fig. 12.8. The illustration shows the cartilaginous models of true and false ribs in a 9-week-old embryo.

Transformation of the cartilaginous ribs into bony ribs begins with deposition of calcium ion in the cartilaginous matrix and degeneration of the matrix. Concurrently with this, ossification centers develop within the degenerating matrix. The matrix is invaded with blood vessels accompanied by progenitors cells which in this vascular environment differentiate into osteoblasts that lay down bony (osseous) tissue that replaces the cartilage all over the rib model yielding bong ribs. The original site where the costal processes were connected to the vertebrae are replaced by the costovertebral synovial joints.

Fig. 12.9. The illustrations show the development of ribs in close association with the development of the vertebrae. Both develop from the sclerotome. The are of the sclerotome that gives rise to rib is shown in orange colour, whereas those parts of the sclerotome that give rise to various parts of the vertebra are shown in purple and green colors.

The Sydesmotomes

The sydesmotome is that part of the somites which give rise to connective tissues particularly those giving rise to ligaments and tendons. It plays a significant role in the development of musculoskeletal system. Similar to other parts of the somites, the sydesmotome is of mesodermal origin. Mesenchymal cells of the sydesmotome differentiate into fibroblast that secrete the ground substance and types of connective tissue fibers, namely collagen, elastic fibers and reticular fibers. The relative amount of cells and fibers vary resulting in different types of connective tissues classified into dense and loose connective tissues. Mesenchyme itself is a loose embryonic connective tissue, made of mesenchymal cells that are undifferentiated multipotent cells. This process is directed by specific transcription factors and signaling biomolecules. Sydesmotome is closely related to sclerotomes and to bones and cartilage that develop from the sclerotome.  Thus, syndesmoses are appropriately positioned to differentiate into joints and associated connective tissue ligaments.

The Myotomes

Myotomes are those segments of somites that develop into both axial and appendicular skeletal muscle and associated connective tissues. Being part of somites, myotomes are segmented in nature. The myotomes are made progenitor cells that differentiate into myogenic cells called myoblasts. In addition to myogenic cells, myotomes contain mesenchyme which support the myogenic cells and surround them ultimately forming endomysium, perimysium, perimysium and tendons. The mesenchyme participates effectively in the differentiation of myogenic cells, organization of muscles fibers and segregation of muscles.  

Myoblasts which develop from the myotomes proliferate by mitosis, align themselves, and secrete fibronectin, a biomolecule that facilitates fusion of the myoblasts. In this way, myotubes, which are multinucleated structures, are formed. Within the myotubes, actin filaments and myosin filaments are synthesized by rER. Well organized arrangement of the actin and myosin filaments results in the formation of the myofibrils, which are the contractile units of skeletal muscle. With the increase in number of myofibrils, the nuclei of myotubes are pushed peripherally to assume the typical peripheral location of nuclei of skeletal muscle fibers. Several biomolecules organize the differentiation of myogenic cells into skeletal muscle fibers; these include growth factors such as FGF and TGF-β, myogenic regulatory factors such as MyoD and MyF5, and myocyte enhancer factors (MEFs).

Myotomes split into two segments which are the epaxial segment and the hypaxial segment. The epaxial segment develops into the posterior body muscles, whereas the hypaxial segment develops into the anterior body muscles. The head muscles develop from the paraxial mesoderm and from the unsegmented prechordal mesoderm.  The body muscles lying dorsal (posterior) to the vertebral column form the epaxial muscles, whereas those lying ventral (anterior) to the vertebral column form the hypaxial muscle.

Epaxial muscles are present in the back dorsal to the vertebral column; they are true back muscles that are innervated by the dorsal rami of spinal nerves. Epaxial muscles are responsible for extending, flexing, lateral bending, and rotating the spinal column, and as well as providing postural stability.

Epaxial muscles include the erector spinae, the suboccipital muscles, the transverse spinal muscles, the interspinal muscles and the splenius. They are innervated by the posterior branches of the spinal nerves.  Hypaxial muscle which are located from the ventral to the vertebral column include muscle of the body wall, muscle of the diaphragm, intercostal muscles, and muscles of the limbs; they are innervated by the ventral rami of the spinal nerves.

The preaxial neck muscles are located in the anterior regions of the neck and are involved in neck flexion, head movements, and head stabilization. These muscles are also known as the anterior vertebral muscles. They include the longus colli, the longus capitis and the rectus capitis.

Fig. 12.10. The illustrations show epaxial and hypaxial muscle groups. The illustration on the left is of the thoracic region, whereas the illustration on the right is of the abdominal region. The dorsal and ventral rami of the spinal nerves are also shown. Epaxial muscles originate at a level dorsal (poster0 to the vertebral column (in blue colour), whereas the hypaxial muscles originate at levels ventral (anterior) to the vertebral column.

Development of the Limbs

The first indication for the development of the limbs is the appearance of the two pairs of limb buds in the 4^th week of embryonic development; these are the primordia of the arms and legs. They are thickenings of the mesenchyme covered by ectoderm that bulge from the ventrolateral body wall. The buds of the arms (upper limb) appear before the appearance of buds of the legs (lower limb), which show up a few days later. The mesenchymal cells originate from the somatic plate of the lateral mesoderm. The process of limb developments is controlled by hox genes, T-box proteins, and fibroblast growth factors. The ectoderm covering the distal end of the limb bud is called the apical ectodermal ridge which overlies the zone of proliferation that caps the core of proliferating mesenchymal cells. Proliferation of the mesenchymal cells results in the elongation of the limb bud in a ventral direction. Some of the mesenchymal cells differentiate into chondroblasts that secrete a matrix of hyaline cartilage forming cartilaginous models of the limb bones. Elongation and enlargement of the cartilaginous modes takes place by interstitial and appositional growth. Interstitial growth results from proliferation of chondrocytes within the cartilage, whereas appositional growth results from mesenchymal cells on the surface of the model differentiating into chondroblasts that lay new layers of cartilage on top of the existing cartilage. The apical ectodermal ridge breaks up facilitating formation of the digits, which takes place at about the 6^th week of embryonic development. A characteristic feature of this process is the appearance of digital rays and separation of the digits as a result of apoptosis of the cells in between the developing digits.   

Fig. 12.11.  The illustrations show the process of development of the form limb (arm) from the limb bud (left) to elongation of the bud and formation of the cartilaginous models of the arm bones, and hand plate (middle), to formation of the hand digits. During formation of the digits, the apical ectoderm ridge (AER) degenerates is maintained above the digital rays (red arrows) and degenerates in between (green arrows). The mesenchymal cells present between the rays undergo apoptosis and the digits get separated from each other.

Ossification Centers

Bones develop by two methods known as intramembranous ossification and endochondral ossification. Intramembranous ossification is a method of bone formation whereby osseous (bony) tissue develops directly from the mesenchyme. The mesenchymal cells aggregate and differentiate into osteoblasts that secrete the bone matrix, thus forming a new. Flat bones of the skull are examples of bones that develop by intramembranous ossification. In the other method of bone formation, which is called endochondral ossification, a cartilaginous model of the bone is first formed. It is a model of hyaline cartilage which resembles in shape the definitive bone. This cartilage model is then replaced by formation of ossification centers in the model. Models of long bones such as the femur, humerus, tibia and radius often show two or more centers of ossification, a primary center of ossification and one or more secondary centers of ossification. Calcium is deposited in the cartilage matrix in the center of ossification; this leads to death of chondrocytes and degeneration of the cartilage. The degenerating matrix is invaded by blood vessels which bring into the region osteoprogenitor cells that differentiate into osteoblasts that lay down osseous (bone) tissue. The first center of ossification to appear is called the primary center of ossification is in the middle of the shaft of the bone model. The secondary ossification centers develop in a similar manner but in head ends of the model. The artery supplying the primary center of ossification becomes the nutrient artery of adult bones and the opening they pass through across the bony tissue is called the nutrient foramen. The newly formed bone in the centers of ossification expand and approach each until cartilage is completely replaced in model, except in the border between the shaft and the head where hyaline cartilage is present forming the epithelial growth plate, and head surface forming the articular cartilage. Long bone elongation depends on widening of the epiphyseal plate and the subsequent replacement of cartilage by bone. This is crucial for growth of children and young adults and does stop except after closure of the epiphyseal plate in the twenties of age.

Fig. 12.12. The illustration shows the cartilaginous model of a long bone (far left), and its transformation into a long osseous bone (far right) by the processes of formation of primary and secondary ossification centers. After completion of bone formation hyaline cartilage is present only the epiphyseal plates and the articular surfaces.

Development of Joints

Bones are joined together by structures known as joints, that allow both movement and stability of the joined bones. Joints are of three structural types which fibrous joints, cartilaginous joints and synovial joints.

Fibrous joints where articulating bones are connected by a dense fibrous connective tissue such as those present between bones of the skull. This type of joint does not allow movement of the articulating bones; joints that do not allow movements of bones are referred to synarthroses. Cartilaginous joints are joints where the articulating bones are connected by hyaline cartilage or fibrocartilage. This type of joints allows limited movements of the articulating bone and is known as amphiarthroses. It is found between the vertebrae and between the vertebrae and the ribs. The third type of joints is the synovial joint, which is the most common type of joints; it allows for a wide range of movements. It is characterized by a fluid filled cavity surrounded by a capsule and articular hyaline cartilage; the best-known example is the knee joint. Other known synovial joints include the elbow joint, the hip joint, and the finger joints. The joint capsule which surrounds the joint and holds together the articulating bones is lined with the synovial membrane. it is type-B cells of the synovial membrane that secrete the synovial fluid.

Fig. 12.13.  The illustration on the left shows characteristics and components of a synovial joint, whereas illustration on the right shows characteristics of a cartilaginous joint, the pubic symphysis.

Joints develop during embryogenesis concurrently with the development of the bone they hold together. They develop from the mesenchyme from which the bone develops. The mesenchyme between adjacent ends of the two bones to be articulated may develop into a dense connective tissue anchoring the two bones and forming a fibrous joint or may develop into hyaline or fibrocartilage anchoring the two bone and forming a cartilaginous joint. Development of most synovial joints takes place during development of the limb buds commencing on the 6^th week of embryonic development concurrent with the formation of the cartilaginous models of bones. The joint interzone appears between the adjacent cartilaginous models. Apoptosis of mesenchymal cells within center of the joint interzone leads to formation of a space. The mesenchymal cells surrounding the space laterally differentiate into fibroblasts the produce a tough dense connective tissue that anchors the cartilaginous models surrounding the space, Medial to the capsule, the mesenchymal cells differentiate into type-2 synovocytes that secrete a viscid fluid, the synovial fluid, which fills the space which is now known as the synovial cavity.

Fig. 12.14. The illustrations show the steps of development of synovial joint. In the far left the mesenchyme has differentiated into hyaline cartilage and the surrounding connective tissue perichondrium. The mesenchyme in between the cartilage models remains unchanged and is referred to as the homogenous interzone. In the next illustration, the homogenous interzone differentiates into a 3-layered interzone. Next to the right cavities develop within the interzone and interzone becomes surrounded by dense fibrous layer, the joint capsule. In the far right, the interzone spaces coalesce and the joint cavity surrounded by the synovial membrane and the joint capsule.

Development of the Skull

The embryonic development of the skull involves development of head mesenchyme, formation of bone by both intramembranous ossification and endochondral ossification. Then the neurocranium (cranial base and vault) and the viscerocranium (fascial skeleton) develop.

The first step in the development of the cranium is the differentiation of mesenchyme from the paraxial mesoderm and neural crest cells. The paraxial mesoderm contributes to the formation of neurocranium while the neural crest cells contribute to development of both the neurocranium and viscerocranium. The mesenchyme then condenses to form the first recognizable skull elements. Intramembranous Ossification occurs within the condensed mesenchyme where mesenchymal cells differentiate into osteoblasts that synthesize and secrete the bone matrix. In this way the flat bones of the skull, including the frontal bone, the parietal bone, the occipital bone, the temporal bone, and some facial bones are formed. Some other bones of the skull formed by endochondral ossification where mesenchymal cells first differentiate into chondroblast that synthesize and secrete a matrix of hyaline cartilage. Ossification centers develop within these models, transforming them into osseous bones. Skull bones that develop by endochondral ossification include the ethmoid, the sphenoid, and the occipital, as well as the petrous and mastoid parts of the temporal bone. In addition, the mandibular condyles and angles are also formed by endochondral ossification. The skull bones are articulated with each other by sutures, which are fibrous joints made of connective tissue that allow for continued growth of the skull as the brain expands.

Fig. 12.15. The illustration on the left shows the viscerocranial bones (in colors) and the neurocranium (in white). The illustration on the right shows developing neurocranial bones (in pink) and the developing sutures in between (in white).

Fig. 12.16. Classification of bones of neurocranium and viscerocranium based on ossification type.

Take a quiz