Figure 8. Hypothesized signaling mechanisms of CTGF. A, The11 kDa human recombinant CTGF peptide inhibited endogenous myelination in culture. This particular peptide contained only the C terminus and all of its binding domains. Unlike the full-length CTGF, it lacked, among other things, the IGF binding domain, said to underpin the previously published mechanisms by which CTGF inhibits oligodendrocyte maturation. B, Our results have shown that SCM, which contains CTGF, and/or CTGF alone significantly, reduced the differentiation of purified OPCs in culture. This direct inhibition of oligodendrocyte maturation could be the result of the sequestering of vital promyelinating factors by CTGF, or via the CTGF-induced modulation of the ECM, which is known to mediate aspects of process extension in oligodendrocytes. SC-secreted CTGF (and other possible factors) could also affect myelination indirectly, by enhancing astrocyte reactivity. Reactive astrocytes may alter their expression of mediators of myelination, such as BMP4 or IGF2, which in turn downregulate vital transcriptional factors in oligodendrocytes (i.e., Olig1 and Olig2). Furthermore, as reactive astrocytes are also a source of CTGF after injury, this could exacerbate the SC-induced block on oligodendrocyte differentiation by enhancing the bioavailability of CTGF at the lesion site. Because of the highly complex nature of the CTGF molecule, it is possible that CTGF affects myelination through multiple pathways. Furthermore, its signaling mechanisms are also likely to involve several unknown mediators of glial and neuronal cell behavior, culminating in this reduction in oligodendrocyte myelination.