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INTRODUCTION TO : The Embryology of the Skeletal System
The skeletal system develops from paraxial and lateral plate (somatic layer)
mesoderm and from neural crest. Paraxial mesoderm forms a segmented
series of tissue blocks on each side of the neural tube, known as
somitomeres in the head region and somites from the occipital region
caudally. Somites differentiate into a ventromedial part, the sclerotome, and a
dorsolateral part, the dermomyotome. At the end of the fourth week
sclerotome cells become polymorphous and form a loosely woven tissue, the
mesenchyme, or embryonic
connective tissue. It is
characteristic for
mesenchymal cells to migrate and to differentiate in many ways. They may
become fibroblasts, chondroblasts, or osteoblasts (bone-forming cells).
. The bone-forming capacity of mesenchyme is not restricted to cells of the
sclerotome, but occurs also in the somatic mesoderm layer of the body
wall, which contributes mesoderm cells for formation of the pelvic and
shoulder girdles and the long bones of the limbs. Neural crest cells in the
head region also differentiate into mesenchyme and participate in formation of
bones of the face and skull. Occipital somites and somitomeres also contribute
to formation of the cranial vault and base of the skull. In some bones, such as
the flat bones of the skull, mesenchyme in the dermis differentiates directly
into bone, a process known as intramembranous ossification. In most bones,
however, mesenchymal cells first give rise to hyaline cartilage models, which in
turn become ossified by endochondral ossification.
The skull can be divided into two parts: the neurocranium, which forms a
protective case around the brain, and the viscerocranium, which forms the
skeleton of the face. The neurocranium is most conveniently divided into two
portions: (a) the membranous part, consisting of flat bones, which surround
the brain as a vault; and(b) the cartilaginous part, or chondrocranium, which
forms bones of the base of the skull.
Newborn Skull
At birth the flat bones of the skull are separated from each other by
narrow seams of connective tissue, the sutures, which are also derived from
two sources: neural crest cells (sagittal suture) and paraxial mesoderm (coronal
suture). At points where more than two bones meet, sutures are wide and
are called fontanelles. The most prominent of these is the anterior
fontanelle, which is found where the two parietal and two frontal bones
meet. Sutures and fontanelles allow the bones of the skull to overlap
(molding) during birth.
Clinical implications
Cranial defects and skeletal dysplasias
Neural crest cells- these originate in the neuroectoerm from facial skeleton and
most of the skull.
Craniosis- the cranial vault fails to form cranioschsis meaning that the brain tissue
exposed to amniotic fluid degenerates ( anencephaly).
Microcephaly- the brain fails to grow and the skull fails to expand.
Craniosynostosis and dwarfism
Acromegaly- this is caused by hyperpitutarisum and production of growth
Achondroplasia- this affects long bones and spinal curve problem
Thanalophoric- neonathal form of dwarfism: they are two types. Type 1: short
curved femur
Type 2: long femurs
After four weeks of development, the buds for the limbs become visible from the
ventrolateral body wall. It consists of a mesenchymal core that will form the
bones and connective tissues of the limb which is covered by a layer of cuboidal
ectoderm. The ectoderm at the distal border of the limb then becomes thicker
which forms after the apical ectodermal ridge (AER). As the limbs continue
growing, the cells that are farther away from, the influence of AER begins to form
into muscles and cartilage.
5 weeks
6 weeks
The limb buds develop as the embryo grows
The limb buds of the six week embryo now become flattened to form the hand
plates and foot plates which is separated by a circular constriction. Fingers and
toes are formed.
Development of the upper and lower limb is similar except that the
morphogenesis of the lower limb is approximately one to two days behind that of
the upper limbs. During the seventh week of gestation, the limbs (both upper and
lower) rotate in opposite directions. The upper limbs rotates ninety degrees
laterally so that the extensor muscles lie on the lateral posterior surface and the
thumbs lie laterally, meanwhile the lower limbs rotates ninety degrees medially
placing the extensor muscles on an anterior surface and the big toe medially.
By the sixth week of development of the embryo the first hyaline cartilage models
are formed by chondrocytes. Joints are now formed in the cartilaginous
condensations. Cells in this region then increase in number and in density and join
a cavity that is formed by cell death. Ossification of the bones of the extremities,
endochondral ossification begins by the end of the embryonic period. The primary
ossification centers are present in all of the long bones of the limbs of the embryo
by the twelfth week of development.
At birth the diaphysis of the bones are usually completely ossified but the two
ends; the epiphyses are still cartilaginous. A temporary a cartilage plate remains
between the diaphyseal epiphyseal ossification centers. The epiphyseals plate
plays an important role in growth and length of the bones of the embryo. When
the bones has acquired its full length, the epiphyseal plates disappear and the
epiphyses then unite with the shaft of the bone. In long bones an epiphyseal plate
is formed in each extremity in smaller bones, such as the phalanges; it is found
only at one extremity and in irregular bones such as the vertebrae one or more
primary centers of ossification.
Positioning of the limbs along the cranio - caudal axis in the flank regions of the
embryo is regulated by the HOX genes expressed along this axis.
Thesehomeoboxgenes are expressed in overlapping patterns from head to tail,
with some having more cranial limits than others. For example, thecranial limit of
expression of HOXB8 is at the cranial border of the forelimb,and misexpression of
this gene alters the position of these limbs.Once positioning along the
craniocaudal axis is determined, growth mustbe regulated along the
proximodistal, anteroposterior, and dorsoventral axes.Limb outgrowth, which
occurs first, is initiated by FGF-10 secretedby lateral plate mesoderm cells. Once
outgrowth is initiated, bone
morphogenetic proteins (BMPs), expressed in ventral ectoderm, induce formation
of the AER by signaling through the homeobox gene MSX2. Expression ofRadical
fringe (a homologue of Drosophila fringe), in the dorsal half of the limb ectoderm,
restricts the location of the AER to the distal tip of the limbs. This gene induces
expression of Ser-2, a homologue of Drosophila serrate, at the border between
cells expressing Radical fringe and those that are not. It is at this border that the
AER is established. Formation of the border itself is assisted by expression of
Engrailed-1 in ventral ectoderm cells, since this gene represses expression of
Radical fringe. After the ridge is established, it expresses FGF-4and FGF-8, which
maintain the progress zone, the rapidly proliferating population of mesenchyme
cells adjacent to the ridge. Distal growth of the limb is then effected by these
rapidly proliferating cells under the influence of the FGFs. As growth occurs,
mesenchymal cells at the proximal end of the progress zone become farther away
from the ridge and its influence and begin to slow their division rates and to
differentiate. Patterning of the anteroposterior axis of the limb is regulated by the
zoneof polarizing activity (ZPA), a cluster of cells at the posterior border of the
limb near the flank. These cells produce retinoic acid (vitaminA), which initiates
expression of sonic hedgehog (SHH), a secreted factor that regulates the
anteroposterior axis. Thus, for example, digits appear in the proper order, with
the thumb on the radial (anterior) side. As the limb grows, the ZPA moves
distalward to remain in proximity to the posterior border of the AER.
Misexpression of retinoic acid or SHH in the anterior margin of a limb containing a
normally expressing ZPA in the posterior border results in a mirror image
duplication of limb structures (Fig. 8.17). The dorsoventral axis is also regulated by
BMPs in the ventral ectoderm which induce expression of the transcription factor
EN1. In turn, EN1 represses WNT7a expression restricting it to the dorsal limb
ectoderm. WNT7a is secreted factor that induces expression of LMX1, a
transcription factor containing a homeodomain, in the dorsal mesenchyme. LMX1
specifies cells to be dorsal, establishing the dorsoventral components. In addition,
WNT7a maintains
SHH expression in the ZPA and therefore indirectly affects
anteroposteriorpatterning as well. These two genes are also intimately linked in
signaling pathways in Drosophila, and this interaction is conserved in vertebrates.
In fact, all of the patterning genes in the limb have feedback loops. Thus, FGFs in
the AER
activateSHH in the ZPA, while WNT7a maintains the SHH signal. Although
patterning genes for the limb axes have been determined, it is the HOX genes that
regulate the types and shapes of the bones of the limb (Fig. 8.15D). Thus, HOX
gene expression, which results from the combinatorial expression of SHH, FGFs,
and WNT7a, occurs in phases in three places in the limb that correspond to
formation of the proximal (stylopod), middle (zeugopod), and distal (autopod)
parts. Genes of the HOXA and HOXD clusters are the primary determinants in the
limb, and variations in their combinatorial patterns of expression may account for
differences in forelimb and hindlimbstructures. Just as in the craniocaudal axis of
the embryo, HOX genes are nested in overlapping patterns of expression that
somehow regulate patterning.
Bone Age
Radiologists use the appearance of various ossification centers to determine
whether a child has reached his or her proper maturation age. Useful information
about bone age is obtained from ossification studies in the hands and wrists of
children. Prenatal analysis of fetal bones by ultrasonography provides information
about fetal growth and gestational age.
Limb Defects
Limb malformations occur in approximately 6/10,000 live births, with 3.4/10,000
affecting the upper limb and 1.1/10,000, the lower. These defects are often
associated with other birth defects involving the craniofacial, cardiac, and
genitourinary systems. Abnormalities of the limbs vary greatly, and they may be
represented by partial (meromelia) or complete absence (amelia) of one or more
of the extremities. Sometimes the long bones are absent, and rudimentary hands
and feet are attached to the trunk by small, irregularly shaped bones
(phocomelia, a form of meromelia) (Fig. 8.18, Aand B). Sometimes all segments of
the extremities are present but abnormally short (micromelia). Although these
abnormalities are rare and mainly hereditary, cases of teratogen-induced limb
defects have been documented. For example, many children with limb
malformations were born between 1957 and 1962. Many mothers of these
infants had taken thalidomide, a drug widely used as a sleeping pill and
antinauseant. It was subsequently established that thalidomide causes a
characteristic syndrome of malformations consisting gross deformities of the long
bones, intestinal atresia, and cardiac anomalies.Since the drug is now being used
to treat AIDS and cancer patients, there isconcern that its return will result in a
new wave of limb defects. Studies indicatethat the most sensitive period for
teratogen-induced limb malformations
is the fourth and fifth weeks of development. A different category of limb
abnormalities consists of extra fingers or toes (polydactyly) (Fig. 8.19A). The extra
digits frequently lack proper muscle connections. Abnormalities with an excessive
number of bones are mostly bilateral, while the absence of a digit such as a
thumb (ectrodactyly) is usually unilateral. Polydactyly can be inherited as a
dominant trait but may also be induced by teratogens. Abnormal fusion is usually
restricted to the fingers or toes (syndactyly). Normally mesenchyme between
prospective digits in the handplates and footplates breaks down. In 1/2000 births
this fails to occur, and the result is fusion of one or more fingers and toes (Fig.
8.19B). In some cases the bones actually fuse.
Cleft hand and foot (lobster claw deformity) consists of an abnormal cleft
between the second and fourth metacarpal bones and soft tissues. The third
metacarpal and phalangeal bones are almost always absent, and the thumb and
index finger and the fourth and fifth fingers may be fused (Fig.
8.19C ). The two parts of the hand are somewhat opposed to each other and act
like a lobster claw.
The role of the HOX genes in limb development is illustrated by two abnormal
phenotypes produced by mutations in these genes: Mutations in HOXA13result in
hand-foot-genital syndrome, characterized by fusion of the carpal bones and
small short digits. Females often have a partially (bicornuate) or completely
(didelphic) divided uterus and abnormal positioning of the urethral orifice. Males
may have hypospadias. Mutations in HOXD13 result in a combination of
syndactyly and polydactyly(synpolydactyly).
Clubfoot usually accompanies syndactyly. The sole of the foot is turned inward,
and the foot is adducted and plantar flexed. It is observed mainly in males and in
some cases is hereditary. Abnormal positioning of the legs in utero may also cause
Congenital absence or deficiency of the radius is usually a genetic abnormality
observed with malformations in other structures, such as
craniosynostosis–radial aplasia syndrome. Associated digital defects, which may
include absent thumbs and a short curved ulna, are usually present.
Amniotic bands may cause ring constrictions and amputations of the limbs or
digits (Fig. 8.20). The origin of bands is not clear, but they may represent
adhesions between the amnion and affected structures in the fetus. Other
investigators believe that bands originate from tears in the amnion that
detach and surround part of the fetus.
Congenital hip dislocation consists of underdevelopment of the acetabulum and
head of the femur. It is rather common and occurs mostly in females. Although
dislocation usually occurs after birth, the abnormality of the bones develops
prenatally. Since many babies with congenital hip dislocation are
breech deliveries, it has been thought that breech posture may interfere with
development of the hip joint. It is frequently associated with laxity of the
Vertebral Column
It is during the fourth week of development that cells of the sclerotomes shift
their position to surround both the spinal cord and the notochord . This
mesenchymal column retains traces of its segmental origin, as the sclerotomic
blocks are separated by less dense areas containing intersegmental arteries.
During further development the caudal portion of each sclerotome segment
proliferates extensively and condenses.
This proliferation is so extensive that it proceeds into the subjacent
intersegmental tissue and binds the caudal half of one sclerotome to the cephalic
half of the subjacent sclerotome. Hence, by incorporation of the intersegmental
tissue into the precartilaginous vertebral body, the body of the vertebra becomes
intersegmental. Patterning of the shapes of the different vertebra is regulated by
HOX genes.
Mesenchymal cells between cephalic and caudal parts of the original sclerotome
segment do not proliferate but fill the space between two precartilaginous
vertebral bodies. In this way they contribute to formation of the intervertebral
disc. Although the notochord regresses entirely in the region of
the vertebral bodies, it persists and enlarges in the region of the intervertebral
disc. Here it contributes to the nucleus pulposus, which is later surrounded by
circular fibers of the annulus fibrosus. Combined, these two structures form
the intervertebral disc.
Rearrangement of sclerotomes into definitive vertebrae causes the myotomes to
bridge the intervertebral discs, and this alteration gives them the capacity to
move the spine. For the same reason, intersegmental
arteries, at first lying between the sclerotomes, now pass midway over the
vertebral bodies. Spinal nerves, however, come to lie near the intervertebral discs
and leave the vertebral column through the intervertebral foramina.
Development of Ribs and Sternum
Ribs form from the costal processes of thoracic vertebrae and are derived from
the sclerotome portion of paraxial mesoderm. The sternum develops separately
in somatic mesoderm in the ventral body wall. Two sternal bands are
formed on either side of the midline, and these later fuse to form cartilaginous
models of the manubrium, sternebrae, and xiphoid process.
Illustration showing the manner in which each vertebral centrum is developed
from portions of two adjacent segments. (Bartleby)
Sadlar, Thomas W. (2006) Langman’s Medical Embryology (07/21/2013)