**10. Aggrecan and Cellular Regulation**

The form of aggrecan present in the notochord does not contain KS but contains the HNK-1 trisaccharide recognition motif [92] (Figure 3b,e). S103L reactive aggrecan is prominent in the peri-notochordal space and its inhibitory properties on NC cells instructively guides their migration during formation of the neural tube and notochord [90,91] (Figure 9). The absence of KS on aggrecan is not without precedent. Rodent aggrecan has a truncated core protein and also does not contain a KS rich region; however, this is not detrimental to its weight-bearing properties in cartilage or the turnover of aggrecan by MMPs in these tissues. Rodent aggrecan contains small *O*- and *N*-linked KS chains in the G1, IGD and G2 domain described in human aggrecan with roles in the potentiation of ADAMTS-4 and -5 activity. Some studies have also reported the existence of populations of aggrecan devoid of KS in brain tissues based on an absence of reactivity with 5D4 anti-KS antibody, although their detailed characterisations have yet to be provided. Aggrecan expressed by embryonic glial cells in the brain is an astrocyte developmental regulator [186]. Chick aggrecan nanomelia mutants display marked increases in the expression of astrocyte differentiation genes in the absence of extracellular aggrecan indicating that aggrecan regulates astrocyte differentiation and controls glial cell maturation during brain development [186]. Heavily sulphated CS chains on aggrecan and other PGs can bind the midkine family members (midkine and pleiotrophin), and some FGF family members (FGF-1, -2, -16 and -18) provide clues as to how they influence cellular processes [48,187]. Appican in brain tissue [188], a CS-PG synthesised by astrocytes but not by neurons [189], contains embedded CS-E motifs [190] within their CS side chains which interact with heparin-binding neuroregulatory factors [187]. Expression of Appican by astrocytes induces morphological changes in C6 glioma cells and promotes adhesion of neural cells to the ECM [191].

In articular cartilage, the CS chains of aggrecan have major roles in the attraction of water into this tissue which forms the basis of its hydrodynamic viscoelastic properties as a weight-bearing tissue. However the non-reducing terminal regions of the CS chains of aggrecan from articular and growth plate cartilages also contain 4, 6-disulphated CS, and these are likely binding candidates for morphogenetic proteins which show a similar distribution to aggrecan in these tissues [192]. BMP-2, FGFR-3 and IHH co-distribute in growth plate cartilage with the pre-hypertrophic cells [193]. BMP-2, BMP-4 and dual BMP-2/4 knockout mice have severely disturbed shortened growth plate organisation due to decreased chondrocyte proliferation and increased apoptosis [194–196]. Type X collagen expression is also severely down regulated as is MMP-13 expression in BMP-2/4 KO mice.
