Title: 3D distribution of perlecan within intervertebral disc chondrons suggests novel regulatory roles for this multifunctional modular heparan sulphate proteoglycan

Authors: AJ Hayes, J Melrose

Address: Raymond Purves Bone and Joint Laboratories, Level 10, Kolling Institute of Medical Research, B6, Royal North Shore Hospital, St. Leonards, New South Wales 2065 Australia.

E-mail: james.melrose at sydney.edu.au

Abstract: Perlecan is a modular, multifunctional heparan sulphate-proteoglycan (HS-PG) that is present in the pericellular and wider extracellular matrix of connective tissues. In the present study, confocal microscopy was used to study perlecan distribution within intervertebral disc chondrons. Perlecan immunolabel was demonstrated intracellularly and in close association with the cell nucleus within chondrons of both the annulus fibrosus (AF) and nucleus pulposus (NP). This observation is consistent with earlier studies that have localised HS-PGs with nuclear cytoskeletal components. Nuclear HS-PGs have been proposed to transport fibroblast growth factor (FGF)-1, FGF-2 and FGFR-1 into the cell nucleus, influencing cell proliferation and the cell-cycle. Perlecan has well-known interactive properties with FGF family members in the pericellular and extracellular matrix. Perinuclear perlecan may also participate in translocation events with FGFs. The glycosaminoglycan side chains of HS-PGs can modulate chromatin structure by regulating the access of transcription factors to DNA. These mechanisms are consistent with the distribution patterns identified here and previously reported for other HS-PGs, introducing a potentially-novel arena for perlecan in gene regulation. Whilst much is known of the structure and function of perlecan in the pericellular and extracellular matrix, very little is known of any intracellular forms of perlecan. The perlecan labelling patterns described here suggest the possibility of involvement of this HS-PG in an intracrine regulatory system. Future studies should further explore this possibility and the potential for this HS-PG as a novel therapeutic target.

Key Words: Perlecan, intracellular, heparan sulphate, intervertebral disc, Wnt signalling pathway, fibroblast growth factor-2, fibroblast growth factor receptor-1.

Publication date: January 17th 2021

Article download: Pages 73-89 (PDF file)
DOI: 10.22203/eCM.v041a06