Abstract
In this study, we review mechanoregulatory roles for perlecan in load-bearing connective tissues. Perlecan facilitates the co-acervation of tropoelastin and assembly of elastic microfibrils in translamellar cross-bridges which, together with fibrillin and elastin stabilise the extracellular matrix of the intervertebral disc annulus fibrosus. Pericellular perlecan interacts with collagen VI and XI to define and stabilize this matrix compartment which has a strategic position facilitating two-way cell-matrix communication between the cell and its wider extracellular matrix. Cues from the extracellular matrix are fed through this pericellular matrix back to the chondrocyte, allowing it to perceive and respond to subtle microenvironmental changes to regulate tissue homeostasis. Thus perlecan plays a key regulatory role in chondrocyte metabolism, and in chondrocyte differentiation. Perlecan acts as a transport proteoglycan carrying poorly soluble, lipid-modified proteins such as the Wnt or Hedgehog families facilitating the establishment of morphogen gradients that drive tissue morphogenesis. Cell surface perlecan on endothelial cells or osteocytes acts as a flow sensor in blood and the lacunar canalicular fluid providing feedback cues to smooth muscle cells regulating vascular tone and blood pressure, and the regulation of bone metabolism by osteocytes highlighting perlecan’s multifaceted roles in load-bearing connective tissues.
Highlights
These findings suggest that perlecan plays a biomechanical role in the pericellular matrix (PCM) comThese findings suggest that perlecan plays a biomechanical role in the PCM compartment, partment, potentially serving as an additional “integrator” of the various matrix proteins potentially serving as an additional “integrator” of the various matrix proteins focused on focused on this region
extracellular matrix (ECM) networks assembled by cells consisting of perlecan-elastin and perlecan-elastin-collagen type VI assembled by cells are both strong and compliant and contribute to the visco-elastic material properties of tensional and weight-bearing connective tissues
Perlecan is an important component of the PCM and has roles in the assembly and function of structures which connect the cell with its pericellular microenvironment
Summary
Perlecan is a large modular, multifunctional heparan sulphate (HS) proteoglycan (HSPG) that is abundant in vascularized tissues and occurs in poorly and non-vascularized connective tissues such as articular cartilage, intervertebral disc (IVD), meniscus, ligament and in tendon as a hybrid form, where at least one of its HS glycosaminoglycan (GAG) chains is replaced by a chondroitin sulphate (CS) chain [1,2] (Figure 1a). Mast cells synthesize perlecan species with smaller molecular weight core proteins [4] apparently arising from alternative splicing and/or protease cleavages in the immunoglobulin-rich domain IV, generating. 2021, 22, 2716 thesize perlecan species with smaller molecular weight core proteins [4] apparently arising from alternative splicing and/or protease cleavages in the immunoglobulin-rich domain. PGs in their own right [5]. Functional PGs in their own right [5]
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