Impact of perlecan, a core component of basement membrane, on regeneration of cartilaginous tissues

Abstract

As an indispensable component of the extracellular matrix, perlecan (Pln) plays an essential role in cartilaginous tissue function. Although there exist studies suggesting that Pln expressed by cartilaginous tissues is critical for chondrogenesis, few papers have discussed the potential impact Pln may have on cartilage regeneration. In this review, we delineate Pln structure, biomechanical properties, and interactive ligands-which together contribute to the effect Pln has on cartilaginous tissue development. We also review how the signaling pathways of Pln affect cartilage development and scrutinize the potential application of Pln to divisions of cartilage regeneration, spanning vascularization, stem cell differentiation, and biomaterial improvement. The aim of this review is to deepen our understanding of the spatial and temporal interactions that occur between Pln and cartilaginous tissue and ultimately apply Pln in scaffold design to improve cell-based cartilage engineering and regeneration. STATEMENT OF SIGNIFICANCE: As a key component of the basement membrane, Pln plays a critical role in tissue development and repair. Recent findings suggest that Pln existing in the pericellular matrix surrounding mature chondrocytes is actively involved in cartilage regeneration and functionality. We propose that Pln is essential to developing an in vitro matrix niche within biological scaffolds for cartilage tissue engineering.

Keywords: Cartilaginous tissues; Extracellular matrix; Pericellular matrix; Perlecan; Stem cell; Tissue regeneration.

Figure 1.

Schematic illustration of the multidomain structure of human Pln. The core protein of Pln consists of five domains I–V [194]. Domain I is made up of a sperm, enterokinase and agrin (SEA) fold, preceded by three GAG attachment sites. Domain II contains four low-density lipoprotein (LDL) receptor motifs and one isolated immunoglobulin-like (Ig) fold. Domain III is made up of a combination of laminin epidermal growth factor (EGF) and laminin IV type A domains that are connected by disulfide linkages in the laminin EGF domains to form an inflexible rod-like structure. In humans, domain IV consists of 21 repeating Ig C2-type modules that are sequentially linked together. Domain V comprises four EGF motifs, three laminin G, and a fourth variable GAG attachment site.

Figure 2.

Signaling pathways of Pln and effect on cartilage development. (A) FGF signaling and mechanotransduction role. The role Pln plays in regulating cartilage homeostasis is achieved by the formation of the PlnDI-FGF complex. This complex sequesters FGFs from receptors on the cell surface and inhibits the downstream signaling pathway [,,–137]. FGF-2 also plays a mechanotransduction role in cartilage via influencing the ERK signaling pathway [15,84,134,139]. (B) BMP signaling. The roles that BMP signaling plays in chondrogenesis and osteogenesis are regulated by BMP-2 storage in the PlnDI-BMP complex and the delicate balance between ligands and antagonists [–147,149]. (C) CTGF signaling. The interaction between CTGF and PlnDII triggers various intracellular signaling pathways and thus regulates the proliferation and maturation of chondrocytes [29,121,151,152,154,155]. (D) FAK-Src signaling. PlnDIV prevents early cell attachment and promotes cell clustering/condensation by suppressing the FAK/Src signaling pathway, but the receptor is unknown [37,156,157]. (E) VEGF signaling. In the early stage of cartilage development, PlnDI, unbound or bound to VEGF165, stimulates angiogenesis by direct interactions with neuropilin 1 (NRP1), VEGFR2, and NRP1/VEGFR2 co-receptors [164]. In the later stage of cartilage development, PlnDV inhibits angiogenesis via dual receptor VEGF2 and integrin. The endorepellin-induced dual receptor internalization and degradation by the caveosome-mediated pathway is also involved in angiostasis [163,165,171].