Abstract
Failure of axonal regrowth is a major obstacle to the treatment of injuries of the adult central nervous system (CNS), and proteoglycans are strong inhibitory cues. Chondroitin sulfate (CS) proteoglycans are strong inhibitors of neuronal injuries of the adult CNS. Besides CS chains, keratan sulfate (KS) chains are also covalently attached to some proteoglycans. However, the biological significance of KS remains to be not well understood. Here we investigated the role of KS in functional recovery and neural plasticity after spinal cord injury (SCI), using KS knockout mice and KS-degrading enzyme, keratanase II (K-II). Motor function recovery with enhanced axonal regeneration/sprouting was promoted in the KS-deficient mice and KS-degrading rats after the thoracic SCI. In vitro assays also demonstrated that KS proteoglycans were required for the proteoglycan-mediated inhibition of neurite outgrowth after SCI. Unexpectedly, K-II and the CS-degrading enzyme chondroitinase ABC (C-ABC) showed comparable effects in vivo and in vitro, but these two enzymes worked neither additively nor synergistically. These data and further in vitro studies suggested that all the three components of the proteoglycan moiety, i.e., the core protein, CS chains, and KS chains, were required for the inhibitory activity of proteoglycans. Our data indicate that KS is essential for and has a comparable impact as CS on post-injury plasticity. Our study also demonstrated that KS and CS are independently required for the proteoglycan-mediated inhibition of axonal regeneration/sprouting, and KS is a candidate target for the treatment of neuronal injuries.
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Acknowledgments
 We wish to thank K. Kadomatsu (Nagoya University), K. Sakamoto (Nagoya University), and T. Yamashita (Osaka University) for their advising us throughout these studies, K. Suzuki, Y. Kurahashi, and A. Tanaka (Sekagaku Corporation) for performing the stability test of K-II and the HPLC analysis of sugar, M. Sawada (Nagoya University) for guidance with the primary culture of neurons, and N. Ozaki (Nagoya University) for guidance with the sensory tests. We also thank T. Natori (Yamanashi-Gakuin University), M. Iida, Y. Naito, S. Nakashima, N. Misawa, and Y. Miwa (Nagoya University) for their excellent technical assistance.
Conflict of Interest  All authors declare that they have no conflict of interest.
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Imagama, S., Ito, Z., Ando, K., Matsuyama, Y., Nishida, Y., Ishiguro, N. (2014). The Proteoglycan-Degrading Enzymes Promote Functional Recovery After Spinal Cord Injury: Keratan Sulfate and Chondroitin Sulfate. In: Uchida, K., Nakamura, M., Ozawa, H., Katoh, S., Toyama, Y. (eds) Neuroprotection and Regeneration of the Spinal Cord. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54502-6_15
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