|Figure 1a. Cartilage mass arises from undifferentiated mesenchyme. Synovial joints arise in the limbs when the cartilage mass splits into two halves.
|Figure 1b. The interzone is the area of increased cell density that develops along the width of the cartilage, characterized by flattened chondrocytes. Cavitation is an increase in intercellular space caused by cells dissociating in the presence of excess hyaluronic acid (HA) and apoptosis of interzone chondrocytes.
|Figure 1c. The intercellular space fills with fluid, creating cavities that ultimately coalesce into a primitive synovial space. This separates the two halves of previously uniform cartilage mass. Articular cartilage forms from the remainder of the interzone along the edges of the synovial space for the developing bone. For more information on joint formation, see references 19-21.
Members of the TGF-beta superfamily may play roles in immunity, angiogenesis, aging, and embryogenesis.1-3 The family itself is large, currently consisting of 30 molecules. Members include the TGF-betas, GDNFs, Activins/Inhibins, BMPs, and GDFs.1,2
The term GDF (growth/differentiation factor) is derived from the first GDF (GDF-1), a TGF-beta related mouse embryogenesis factor.3 GDF-5 is named for its sequence homology to other GDFs and is synthesized as a 495 amino acid (aa) preproprotein in mouse4 and a 501 aa preproprotein in human.5,6 Following cleavage of an approximately 20 aa signal sequence, the 70 kDa pro-region is proteolytically removed, leaving a 15 kDa, 120 aa mature molecule in both mouse and human. The mature monomer will either form a 25 kDa disulfide-linked homodimer, or a heterodimer with another TGF-beta superfamily member.7,8 There is only one aa difference in the mature region of mouse vs. human GDF-5.6
GDF-5 has a restricted expression pattern. It can be secreted by precartilagenous mesenchymal condensations involved in the formation of digits.5,7 It is also produced by fibroblasts,6,9 articular cartilage chondrocytes,10 and odontoblasts.11 GDF-5 actions may be mediated by the TGF-beta superfamily receptors ALK-6, BMP-RII, or Act-RII.12,13
GDF-5 has a number of diverse activities. It may induce angiogenesis by chemoattracting endothelial cells and upregulating plasminogen activator activity.14 It is also neurotrophic for both dorsal root ganglia neurons15 and dopaminergic neurons of the midbrain.16-18 GDF-5 can stimulate astrocytes, suggesting that its neuroprotective effects may be mediated by astrocytes, and not due to a direct effect on neurons.18
The majority of GDF-5 research has centered on embryogenesis and on the development of joints in particular. GDF-5 has an apparent role in the formation of some synovial joints of the digits. GDF-5 may contribute to the formation of the early cartilage mass by promoting mesenchymal transformation to cartilage (see Figure 1a).22,23 It may also contribute to the formation of the interzone, although GDF-5 does not seem to specify exactly where the interzone forms (see Figure 1b).21,22 Finally, after formation of the synovial cavity (see Figure 1c), GDF-5 may direct tendon and ligament formation around the joint, and induce cartilage expansion (thus bone lengthening) in the residual cartilage of bones associated with the synovial joint.20,22-24
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