Diverse and multifunctional roles for perlecan (HSPG2) in repair of the intervertebral disc

Abstract Perlecan is a widely distributed, modular, and multifunctional heparan sulfate proteoglycan, which facilitates cellular communication with the extracellular environment to promote tissue development, tissue homeostasis, and optimization of biomechanical tissue functions. Perlecan‐mediated osmotic mechanotransduction serves to regulate the metabolic activity of cells in tissues subjected to tension, compression, or shear. Perlecan interacts with a vast array of extracellular matrix (ECM) proteins through which it stabilizes tissues and regulates the proliferation or differentiation of resident cell populations. Here we examine the roles of the HS‐proteoglycan perlecan in the normal and destabilized intervertebral disc. The intervertebral disc cell has evolved to survive in a hostile weight bearing, acidic, low oxygen tension, and low nutrition environment, and perlecan provides cytoprotection, shields disc cells from excessive compressive forces, and sequesters a range of growth factors in the disc cell environment where they aid in cellular survival, proliferation, and differentiation. The cells in mechanically destabilized connective tissues attempt to re‐establish optimal tissue composition and tissue functional properties by changing the properties of their ECM, in the process of chondroid metaplasia. We explore the possibility that perlecan assists in these cell‐mediated tissue remodeling responses by regulating disc cell anabolism. Perlecan's mechano‐osmotic transductive property may be of potential therapeutic application.