The upper and lower limb initially develops as a small bulge called a limb bud, which appears on the lateral side of the early embryo. The upper limb bud appears near the end of the fourth week of development, with the lower limb bud appearing shortly after.
Initially, the limb buds consist of a core of mesenchyme covered by a layer of ectoderm. The ectoderm at the end of the limb bud thickens to form a narrow crest called the apical ectodermal ridge. This ridge stimulates the underlying mesenchyme to proliferate rapidly, producing the outgrowth of the developing limb. As the limb bud elongates, cells located farther from the apical ectodermal ridge slow their rates of cell division and begin to differentiate. In this way, the limb develops along a proximal-to-distal axis.
During the sixth week of development, the distal ends of the upper and lower limb buds expand and flatten into a paddle shape. This region will become the hand or foot. The wrist or ankle areas then appear as a constriction that develops at the base of the paddle. Shortly after this, a second constriction on the limb bud appears at the future site of the elbow or knee. Within the paddle, areas of tissue undergo cell death, producing separations between the growing fingers and toes. Also, during the sixth week of development, mesenchyme within the limb buds begins to differentiate into hyaline cartilage, which will form models of the future limb bones.
The early outgrowth of the upper and lower limb buds initially has the limbs positioned so that the regions that will become the palm of the hand or the bottom of the foot are facing medially toward the body, with the future thumb or big toe both oriented toward the head. During the seventh week of development, the upper limb rotates laterally by 90 degrees so that the palm of the hand faces anteriorly and the thumb points laterally. In contrast, the lower limb undergoes a 90-degree medial rotation, bringing the big toe to the medial side of the foot.
All of the girdle and limb bones, except for the clavicle, develop by the process of endochondral ossification. By the twelfth week, a primary ossification center appears in the diaphysis (shaft) region of the long bones, initiating the process that converts the cartilage model into bone. A secondary ossification center will appear in each epiphysis (expanded end) of these bones at a later time, usually after birth. The primary and secondary ossification centers are separated by the epiphyseal plate, a layer of growing hyaline cartilage. This plate is located between the metaphysis and each epiphysis. It continues to grow and is responsible for the lengthening of the bone. The epiphyseal plate is retained for many years until the bone reaches its final adult size, at which time the epiphyseal plate disappears, and the epiphysis fuses to the metaphysis.
The clavicle is the first bone to begin ossification, with ossification centers appearing during the fifth week of development. Initially, two ossification centers form from intramembranous ossification and fuse to form the middle of the clavicle. Then endochondral ossification occurs at both the medial and lateral ends after birth, with the medial epiphysis being the last bone site to complete ossification in the body.
During this process, mesenchymal cells differentiate directly into bone-producing cells, which produce the clavicle directly without first making a cartilage model. Because of this early production of bone, the clavicle is the first bone of the body to begin ossification, with ossification centers appearing during the fifth week of development. However, the ossification of the clavicle is not complete until age 25.
This text is adapted from Openstax, Anatomy and Physiology 2e, Section 8.5: Development of the Appendicular Skeleton.
