Hyaluronic acid is a normal component of the extracellular matrix in the CNS. I believe I'm right in saying that it's actually supposed
to inhibit oligodendrocytes precursors from maturing – that's part of its job. It's part of the complicated switching on and switching off that goes on during development, but it's supposed to be down-regulated after. Two other components of the extracellular matrix also seem to play a role in active lesions: Vitronectin and Fibronectin. I'm sorry for the long extracts, but I think the ECM is starting to look very interesting:
Membrane-associated Syndecans, glypicans Cell adhesion, binding of growth factors Bernfield et al. (1992),
Hyaluronan Cell division and motility, ECM–ECM
interactions, inhibition of the differentiation
of oligodendrocyte progenitors
Bignami et al. (1993)
A high molecular weight (HMW) form of the GAG hyaluronan accumulates in demyelinating MS lesions and in the brain tissue of experimental autoimmune encephalomyelitis mice, a widely used animal model to study MS pathology (Back et al. 2005). Back and co-workers demonstrated that the HMW form of hyaluronan inhibits remyelination in an experimental demyelination animal model. HMW hyaluronan inhibits the maturation of oligodendrocyte precursors into myelin-forming oligodendrocytes. These findings suggest that deposition of HMW hyaluronan in MS lesions may contribute to lesion progression by blocking the maturation of oligodendrocyte precursor cells.
In the CNS, vitronectin plays a role in the induction of neurite outgrowth in development (Grabham et al. 1992; Martinez-Morales et al. 1995). Vitronectin is primarily synthesized in the liver (Tomasini and Mosher 1991) and has affinity for different integrins expressed on T-cells, platelets, endothelial cells and macrophages. In normal adult CNS, vitronectin is localized to most blood vessels with the exception of capillaries, suggesting that small amounts of vitronectin are deposited in the CNS under normal conditions. In active demyelinating MS lesions vitronectin expression was strikingly enhanced in blood vessel walls, at the border of chronic active MS lesions, in demyelinated axons and on a small number of hypertrophic astrocytes (Sobel et al. 1995). The functional role of vitronectin under inflammatory conditions is still unknown, however it has been shown that vitronectin promotes neurite outgrowth (Neugebauer et al. 1991) and affects cellular migration of astrocytes (Milner et al. 1999). As vitronectin mRNAwas undetectable in normal adult brain (Gladson et al. 1995), it might be synthesized by infiltrating leukocytes or derived from plasma as a result of BBB breakdown.
Fibronectin is an HMW glycoprotein that exists as an insoluble glycoprotein dimer, which serves as a linker in the ECM, and as a soluble disulfide linked dimer found in the plasma. The plasma form is synthesized by hepatocytes, while the ECM form is produced by fibroblasts, endothelial cells and macrophages (Stenman and Vaheri 1978; Tamkun and Hynes 1983). Fibronectin is involved in cellular interaction by binding to different components of the ECM and to membrane-bound fibronectin receptors on cell surfaces. In normal CNS tissue, fibronectin is expressed in the adventitia of parenchymal and leptomeningeal blood vessels and in the choroid plexus (Esiri and Morris 1991). In MS brain tissue enhanced fibronectin deposition was primarily localized to vessel walls, in particular in perivascular infiltrates, and correlated with the extent of inflammation. Fibronectin accumulation was also detected in the parenchyma of active demyelinating MS lesions suggesting that, in addition to extravasation from affected blood vessels, fibronectin may be locally produced by endothelial cells or infiltrated macrophages in the CNS (Sobel and Mitchell 1989; Esiri and Morris 1991). Recent data demonstrated that fibronectin inhibits the differentiation of oligodendrocyte progenitors and thus remyelination
Nowadays, the definition of the ECM is broadened and basically includes all secreted molecules that are immobilized outside cells. Table 1 provides an overview on the distinct ECM components of the CNS and their major functions. Generally, the ECM of the CNS is involved in various regulatory processes in the development and normal function of the CNS, provides physical support for neurons and glial cells and regulates ionic and nutritional homeostasis (Bandtlow and Zimmermann 2000; Yamaguchi 2000). The molecular composition of the ECM in the CNS influences interactions between a variety of molecules and cells, and is specifically involved in growth and regeneration of nerve fibers, but also in programmed cell death of neurons. Insulin-like growth factors (IGFs) are trophic factors in the CNS and are involved in migration and differentiation of oligodendrocyte precursor cells and remyelination of axons by stimulating myelin protein synthesis (Jones and Clemmons 1995). Modes of IGF action are regulated by IGF-binding proteins (IGFBPs), which are secreted in the extracellular space. It has been shown that several IGFBPs, including IGFBP- 2, -3 and-5 bind constituent proteins of the ECM, thereby influencing cellular growth and proliferation (Jones et al. 1993; Conover and Khosla 2003; Martin and Jambazov 2006). Interestingly, many other ECM components are involved in different aspects of oligodendrocyte biology and myelin formation (Table 2). ECM molecules interact via specific ligands, such as integrins, with cell surface receptors and thus provide cellular signals for growth, movement, proliferation, differentiation and, if needed, apoptosis. Consequently, alterations in the localization and composition of the ECM may result in different biological responses and therefore play an important role in disease development and progression. Highly specialized ECM sheets are the basement membranes (BM) that are present at the interface between epithelial and endothelial cells and their surrounding connective tissues. BM not only function as a tissue boundary on which cells are attached, but may also act as a molecular filter with selective permeability for soluble factors and form a highly specialized substrate for cellular differentiation and gene expression (Kalluri 2003). The regulation of ECM production and degradation is a tightly controlled process involving various proteins and Received April 24, 2007; revised manuscript received July 6, 2007; accepted July 9, 2007.
Address correspondence and reprint requests to Jack van Horssen,
Department of Molecular Cell Biology and Immunology, VU University
Medical Center Amsterdam, PO Box 7057, 1007 MB Amsterdam, The
Netherlands. E-mail: firstname.lastname@example.org
Abbreviations used: BBB, blood–brain barrier; BM, basement membrane,
CS-1, connecting segment-1, ECM, extracellular matrix, GAG,
glycosaminoglycan, HMW, high molecular weight, HSPG, heparan
sulfate proteoglycan, IGF, insulin-like growth factor, IGFBP, IGF-binding
proteins, MMP, matrix metalloproteinase, MS, multiple sclerosis,
PG, proteoglycan, SLRP, small leucine-rich PG.