Regulation of FGF-2, FGF-18 and Transcription Factor Activity by Perlecan in the Maturational Development of Transitional Rudiment and Growth Plate Cartilages and in the Maintenance of Permanent Cartilage Homeostasis

Abstract

The aim of this study was to highlight the roles of perlecan in the regulation of the development of the rudiment developmental cartilages and growth plate cartilages, and also to show how perlecan maintains permanent articular cartilage homeostasis. Cartilage rudiments are transient developmental templates containing chondroprogenitor cells that undergo proliferation, matrix deposition, and hypertrophic differentiation. Growth plate cartilage also undergoes similar changes leading to endochondral bone formation, whereas permanent cartilage is maintained as an articular structure and does not undergo maturational changes. Pericellular and extracellular perlecan-HS chains interact with growth factors, morphogens, structural matrix glycoproteins, proteases, and inhibitors to promote matrix stabilization and cellular proliferation, ECM remodelling, and tissue expansion. Perlecan has mechanotransductive roles in cartilage that modulate chondrocyte responses in weight-bearing environments. Nuclear perlecan may modulate chromatin structure and transcription factor access to DNA and gene regulation. Snail-1, a mesenchymal marker and transcription factor, signals through FGFR-3 to promote chondrogenesis and maintain Acan and type II collagen levels in articular cartilage, but prevents further tissue expansion. Pre-hypertrophic growth plate chondrocytes also express high Snail-1 levels, leading to cessation of Acan and CoI2A1 synthesis and appearance of type X collagen. Perlecan differentially regulates FGF-2 and FGF-18 to maintain articular cartilage homeostasis, rudiment and growth plate cartilage growth, and maturational changes including mineralization, contributing to skeletal growth.

Perlecan: Roles in osteoarthritis and potential treating target

“…While the HS chains of perlecan play indispensable roles in embryogenesis and skeletogenesis, they can also inhibit adult tissue repair processes. Degradation of HS in situ improves wound healing and tissue repair through the re-mobilization of previously sequestered FGF-2, which was unavailable to promote tissue repair, as the results demonstrated that heparanase releases FGF-2 in tissues in an activated form, which promotes wound healing [45,103].…”

“…Heparanase in OA cartilage induces catabolic responses [103] but also downregulates anabolic genes. Reduced HS levels, reduced HS sulfation, and alterations in HS fine structure were observed in OA cartilage, which had decreased degenerative OA histopathology scores [43].…”

“…Osteoblasts synthesize abundant levels of heparanase, and hypertrophic chondrocytes of the chondro-osseous junction contain abundant levels of MMP-13, which degrades perlecan in this region, releasing HS and core protein from PlnI. The elevated production of heparanase by osteoblasts and degradation of perlecan-HS releases bound growth factors that stimulate angiogenesis and promote bone formation [18,[103][104][105].…”

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…Wnt proteins are secreted, lipid-modified glycoproteins which form morphogen gradients that direct cellular behaviour to produce these effects [ 28 ]. Wnt proteins however are hydrophobic and poorly soluble in aqueous media, heparan sulfate proteoglycans (HS-PGs) are necessary for the proper activity of Wnt proteins maintaining their solubility and these also transport Wnt proteins aiding in the formation of Wnt gradients in tissues which drive developmental processes [ 29 ]. Wnt binds to the LDLR domain II of perlecan and this acts as a Wnt delivery vehicle in tissue development [ 29 , 30 ].…”

“…Wnt proteins however are hydrophobic and poorly soluble in aqueous media, heparan sulfate proteoglycans (HS-PGs) are necessary for the proper activity of Wnt proteins maintaining their solubility and these also transport Wnt proteins aiding in the formation of Wnt gradients in tissues which drive developmental processes [ 29 ]. Wnt binds to the LDLR domain II of perlecan and this acts as a Wnt delivery vehicle in tissue development [ 29 , 30 ]. HS-PGs are also pericellular and basement membrane ECM components and have roles in synapse stabilization in neural tissues important in synaptic plasticity and neuron interactivity within neural networks of the central and peripheral nervous systems (CNS & PNS, respectively) [ 24 , 27 ].…”