Introduction

Development of the upper limb (Fig. 1.1) can best be understood as a series of ectodermal and mesodermal interactions controlled by a complex system of signalling during embryogenesis. The development starts as a limb bud in the ventrolateral wall of the embryo on the ‘Wolff crest’ 28 days after fertilization. Differentiation of the limb buds occur between the 5th and 8th week.^1–4 The formation of limb buds is induced by the adjacent somites. The bones are formed as mesenchymal condensations that first chondrify then ossify. Limb muscles are formed from myogenic precursor cells that originate in mesodermal somites. The peripheral nerves arise from the neural crest. They migrate and extend their axons later in response to trophic cues, such as ephrins, produced by the muscles and connective tissues.^5,6

Figure 1.1 The development of the upper limb with particular reference to the elbow. The external appearance of the right arm is shown (A, I–IV), with the internal development of the left arm (B, I–IV): I, 32 days; II, 36 days; III, 42 days; IV, 48 days.

Redrawn from Stanley D and Kay NRM (eds). Surgery of the elbow. Hodder Arnold 1998 (fig 1.2, p 2).

Elbow joint development

Table 1.1 Elbow joint development

Prenatal development

The ectodermal covering at the site of each putative limb thickens to form the apical ectodermal ridge (AER). This together with the somatopleuric mesenchyme is called the progress zone. The orientation and progression of limb development are controlled by the progress zone. The differentiation occurs in a proximodistal, craniocaudal and dorsoventral axis. The proximodistal axis is regulated by the progress zone, which is controlled by factors including fibroblast growth factor (FGF), bone morphogenic protein (BMP) and Hox genes.⁷

Craniocaudal polarization is regulated by a small population of mesenchymal cells on the postaxial border of the limb bud termed the zone of polarizing activity, which produces the peptide, sonic hedgehog (Shh).⁸ BMPs and Gremlin, a secreted inhibitor of BMPs, also participate in this pathway; the BMPs produced throughout the limb mesenchyme and in the AER inhibit production of FGFs by the AER.⁵ A key role of Shh is to activate expression of the BMP antagonist Gremlin, thereby preventing this inhibition of FGF expression (Fig. 1.2). The dorsoventral axis (radio-ulnar axis in upper limb) is controlled by the ectoderm of the limb.

Figure 1.2 Positive and negative feedback loops control limb outgrowth and cessation of growth. This model explains how the two loops are used first to promote and then to terminate signals. Arrows indicate activation; the T-shaped red line indicates inhibition. Dashed lines represent diminished regulation. During promotion of outgrowth, the positive regulatory loop increases all signals; Shh produced in the ZPA (green zone) promotes FGF expression in the AER (blue zone). This effect of Shh is mediated through its ability to induce Gremlin. Gremlin in turn antagonizes bone morphogenetic proteins (BMPs), which inhibit FGF action (not shown). The overall effect is thus to promote FGF expression in the AER. The trigger to cessation of growth occurs when AER FGFs are produced at a sufficiently high level that they repress expression of Gremlin (represented by a T-shaped line in the figure). By this stage of development, the limb mesenchyme has grown, which leads to a larger domain of Gremlin expression (red zone). Once Gremlin expression declines, cessation of limb growth occurs (last panel in figure). Gremlin is no longer present to repress BMP signals, and thus BMPs are able to repress FGF expression. Loss of FGF leads to an inability of FGF to maintain Shh expression. Thus growth along all limb axes ceases. (FGFs, fibroblast growth factors; Shh, sonic hedgehog, AER, apical ectodermal ridge; ZPA, zone of polarizing activity; Grem, Gremlin.)

Redrawn from Lyons K and Ezaki M. Molecular regulation of limb growth. J Bone Joint Surg (Am) 2009; 91:47–52.

While the exact mechanism of chondrogenesis is unclear, the Hox genes, BMP, Sox9, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP) play an important role.^9,10 The elbow joint develops from mesenchymal interzones.¹¹