Embryology And Development: Skeletal System

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When an oocyte is fertilised, the resulting zygote undergoes multiple cell divisions until a blastula is formed (2). A blastula is an animal embryo at the early stage of development when it is a hollow ball of cells (3). The blastula then embeds into the endometrial wall in which the outer layer of the blastula becomes the placenta. The rest of the blastula splits into the primary germ layers called the ectoderm, mesoderm and endoderm (3). The ectoderm forms the most exterior germ layer which develops into the skin brain and nervous system (3). The endoderm forms the most interior layer which develops into the gut lining and internal organs (3). The mesoderm which is the middle layer forms the musculoskeletal and circulatory system (3). The musculoskeletal components of the mesoderm will be discussed including any congenital defects associated.

Skeletal Development

Skeletal system develops via three major routes (1). The somites are segments of repeated internal structures that end up generating the axial skeleton (1). The lateral plate mesoderm generates the limb skeleton and the cranial neural crest forms the branchial arch, craniofacial bones and cartilage (1). The skeletal development process begins with accumulation of the paraxial mesoderm under the neural plate causing thinner mesoderm to form laterally (2). The paraxial mesoderm now in two thick segments run along the embryonic disc and by the third week, the two-paraxial mesoderm begin to segment into somites (2). The neural plate folds forming a neural groove (2). The somites now segment further into the lateral plate mesoderm causing separation of the splanchnic and somatic mesoderm (2). Whilst the somites continue to develop, the neural groove fuses dorsally to form a tube (2). The neural crest can then migrate into the mesoderm (2).

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Axial skeleton development:

The ventromedial portion of each somite forms a sclerotome and both the left and right portions aid in forming the vertebra and the intervertebral disc of the axial skeleton (2).

Limb development:

For limb development, cells from the lateral plate mesoderm and the myotome drift to the limb field and multiply to form the limb bud (5). The lateral plate is responsible for the formation of cartilage and skeleton (5). The myotome forms muscles of the limbs (5). Fibroblast growth factors (FGF 7,10) are released by the lateral plate mesodermal cells causing the ectodermal to form the apical ectodermal ridge (AER) (5). The AER then produces FGF 8, 4 which allows the FGF10 signal to remain allowing further proliferation of the mesoderm (5). The area of FGF10 expression is determined by Wnt8c and Wnt2b which is situated in the hindlimb and forelimb respectively (5). Hind limb or forelimb formation is dependent on two T-box containing transcription factors Tbx4 and Tbx5 respectively (5). Both Wnts and FGFs are necessary to maintain limb bud outgrowth, chondrogenic precursor pool viability and competence for mesenchymal cells to undergo chrondrogenesis after removes of Wnts (6).

Cranial development:

Somites first emerge in the occipital area of the embryo (4). The head mesoderm is rostral to the first somite and forms seven cranial somitomeres (4). These somitomeres are the most cephalic part of the mesoderm from the primitive streak and do not condense to form somites (4). The mesoderm then disperses to fill in the head to form the head mesenchyme (4). The head mesenchyme is then accompanied with neural crest cells (4). Neural crest cells specialise with the aid of epithelial mesenchymal transformation (EMT) process via epithelial cells of the neuroectoderm into multipotential migratory cells (4). Cranium is made up of two layers; the neurocranium which surrounds the brain and the viscerocranuim which forms bones of the face (4). The first five somites from the paraxial mesenchyme and the unsegmented somitomeres form the ectoderm via neural crest cells form the neurocranium (4). The viscerocranuim is only formed from the neural crest mesenchyme forming the facial, frontal, sphenoid and squamous temporal bones (4).

Mesenchymal Condensation:

There are two arrangements of osteogenesis which occur via mesenchymal condensation (1). Direct conversion of mesenchymal tissue into bone is called intramembranous ossification (IM) which primarily occurs in the skull (1). Alternatively, mesenchymal cells can also differentiate into cartilage which is later replaced by bone (1). This is called endochondral ossification which occurs in the vertebral column, pelvis and limbs (1).

Intramembranous (IM) ossification:

Condensation of mesenchymal cells in the cranium is propelled by osteoprogenitor cells (4). Mesenchymal cells crowd around an area of potential bone development and condense into compact nodules (4). Some mesenchymal cells develop into capillaries and others develop into osteoblasts which are bone precursor cells (4). Osteoblasts secrete a collagen-proteoglycan matrix which binds calcium salts thus calcifying the osteoid matrix (4). The osteoblasts are separated from the region of calcification by the osteoid matrix (4). In some cases, the osteoblast may remain in the calcified matrix thereby developing into an osteocyte (4). Calcification forms bony spicules which radiate out from the region of osteogenesis that become surrounded by compact mesenchymal cells forming the periosteum (4). Cells in the periosteum facing the bone become osteoblasts and keep depositing osteoid matrix fluid forming layers (4).

At the fourth week of gestation, the head mesenchyme forms the base of the ectomenengial capsules which is the first evidence of skull formation (4). In the same instance, the occipital sclerotomal mesenchyme intensifies around the notochord soon to develop into the hindbrain (4). From this region, the mesenchymal cells spread to form the base of the brain in which the base of the mesenchymatous capsule forms the densest area of the capsule (4). In the fifth week of gestation, the mesenchyme forms the membranous neurocranium (cavalria) which is initially a capsular membrane around the developing brain (4). The membrane is called meninx primitive or primary meninx defining the first sign of the cranial vault appearing on the 30th day of gestation (4). The meninx primitive is made of curved plates of mesenchyme laterally on both sides of the skull wrapping around the brain to fuse with one another (4). The same plates extend to the base of the skull eventually becoming part of the chondrocranium (4). The meninx primitiva encompasses two layers called the endomeninx which aids in forming the leptomeninx and ectomeninx (4). The leptomeninx forms the pia and arachnoid mata and the ectomeninx forms the inner dura mata and the periosteal and endosteal layers which have both osteogenic and chondrogenic properties (4).

IM ossification is governed by the transcription factor CBFA1 (1). The bone morphogenetic proteins (BMP) likely to be involved are BMP 2,4,7 which initiate the neural crest mesenchymal cells to become bone directly (1). This is achieved by BMPs activating the cbfa1 gene in the mesenchymal cells as well as the genes for osteocalcin, osteopontin and other bone specific matrix proteins (1).

Endochondral ossification- The five stages:

  • Stage 1: The mesenchymal cells become chondrocytes with the encouragement of paracrine factors which induce mesenchymal cells to release Pax1 and Scleraxis transcription factors (1). Scleraxis is often found in the mesenchyme from the sclerotome to form cartilaginous precursors to bone in the facial and limb mesenchyme (1).
  • Stage 2: Steadfast mesenchymal cells now condense into compact nodules to distinguish into chondrocytes. N-cadherin is an important initiation factor and N-CAM a maintaining factor (1). The precartilaginous layers express the SOX9 gene responsible for encoding DNA binding proteins (1).
  • Stage 3: Chondrocytes proliferate rapidly moulding the bone whilst secreting cartilage specific extracellular matrix (1).
  • Stage 4: Cessation of chondrocyte division with volume increase to form hypertrophic chondrocytes (1). Large chondrocytes can modify the matrix by adding collagen x and fibronectin to allow for mineralisation by calcium carbonate (1).
  • Stage 5: Cartilage is intertwined with blood vessels subsequently followed by apoptosis of hypertrophic chondrocytes (1). The empty space produced is now bone marrow and chondrocytes surrounding this area transform into osteoblasts (1). Osteoblasts form bone on the moderately damaged cartilage until all the cartilage becomes bone (1).

Hypertrophic chondrocytes are mineralised due to the autocrine release of vesicles into the extracellular matrix containing enzymes for the generation of calcium and phosphate (1). Due to the change in metabolism and mitochondrial membranes, the hypertrophic chondrocytes undergo apoptosis (1).

The initial chondrocytes which are rounder give rise to stacks of flat chondrocytes which are centrally located in the cartilage primordia as longitudinal columns (6). The immature chondrocytes activate transcription factors Sox 5,6,9 and structural collagen proteins type 2, alpha 1 and aggrecan (6). To propel maturation, parathyroid hormone 1 and Indian hedgehog receptors are both expressed giving rise to early hypertrophic chondrocytes (6). The transformed cells now express collagen type X and alpha 1 allowing for loss of Sox and structural collagen protein expression (6). Eventually, the cells producing alpha 1 collagen lose expression and become late hypertrophic chondrocytes now producing vascular endothelial growth factor (VEGF), matrix metalloproteinase 13 (MMP13) and phosphoprotein 1 (6). This is followed by invasion of endothelial cells, osteoclast and osteoblast precursors (6). Osteoblast precursors arise from perichondrium and hypertrophic chondrocytes (6).

Long Bone Growth:

Most skeletal counterparts undergo endochondral ossification except the bone of the cranial vault, parts of the jaw and the medial clavicle which undergo intramembranous ossification (6). Endochondral ossification occurs outwardly both caudally and laterally from the centre of the bone (1). Whilst endochondral ossification is occurring toward the ends of the long bones, the chondrocytes near the ossification front proliferate before hypertrophy allowing the cartilaginous ends to lengthen the bone (1). The cartilaginous ends of the long bones are called epiphyseal growth plates which contain three regions; proliferating chondrocytes, mature chondrocytes and hypertrophic chondrocytes (1). As the epiphyseal plate continues to produce chondrocytes, the bone continues to grow (1).

Figure 6: This figure shows the stages of endochondral ossification in a long bone (6). Diagram A demonstrates mesenchymal condensation and diagram B shows transformation of mesenchymal cells to chondrocytes to hypertrophic chondrocytes in diagram C (6). Diagram D presents the primary ossification centre followed by further blood vessel infiltration and maturation to the secondary ossification centre in diagram H (6).

Primary endochondral ossification begins in the centre of the epiphyses of developing bone (6). Blood vessels penetrate the perichondrium which is covering the hyaline cartilage to form the periosteum (6). Osteoblasts inside the periosteum secrete bone matrix around the hyaline cartilage to form the bone collar (6). The cartilage in the diaphysis calcifies and hollows to form a cavity (6). The periosteal bud which contains blood vessels, nerves, red marrow elements, osteoblasts and osteoclasts invade the formed cavity to form spongy bone which is temporary (6). The spongy bone is removed from the primary ossification centre by osteoclasts to form the medullary cavity (6). Both the medullary cavity and bone enlarge synchronically (6). Chondroblasts place cartilage matrix on the epiphyseal plate which is eventually eroded and replaced by bony spicules on the side facing the medullary cavity (6). This process occurs until late adolescence (7).

There has been identification that the cell shape and cytoskeletal changes can control chrondrogenesis (6). Generally, limb bud mesenchymal cells undergo chondrogenesis when plated at high density, this may also occur at low density, however, cells must be suspended or be present in collagen gels (6). This lead to the supposition that a spherical shape may be the cause of chondrogenesis (6). Recent studies have shown that dedifferentiated primary chondrocytes in a suspensory gel such as alginate can re-introduce expression of the chondrocyte phenotype and cause depolymerisation of the actin cytoskeleton (6).


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