Biomimetic proteoglycans can molecularly engineer early osteoarthritic cartilage in vivo

Phillips, Evan R.; Prudnikova, Katsiaryna; Bui, Tuan; Taylor, Adam J.; Galindo, Diego; Huneke, Richard B.; Hou, Jie; Mulcahey, Mary K.; Marcolongo, Michele

doi:10.1002/jor.24193

Cited by 15 publications

(12 citation statements)

References 42 publications

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“…In accordance with the presented data, biglycan has been previously described to have a mainly pericellular localization in healthy cartilage 32 . Recently, Phillips et al 42 showed that intra‐articular injected biomimetic proteoglycans are capable of diffusing into OA affected cartilage and being deposited into the pericellular region of the chondrocytes. Complexes of biglycan with other small proteoglycans such as matrilin‐1 and decorin have been indicated to act as a link between collagen type VI microfibrils and the extracellular components aggrecan and collagen type II 43 .…”

Section: Discussionsupporting

confidence: 88%

Biochemical changes of the pericellular matrix and spatial chondrocyte organization—Two highly interconnected hallmarks of osteoarthritis

Danalache

Erler

Wolfgart

et al. 2020

Journal Orthopaedic Research

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During osteoarthritis, chondrocytes change their spatial arrangement from single to double strings, then to small and big clusters. This change in pattern has recently been established as an image‐based biomarker for osteoarthritis. The pericellular matrix (PCM) appears to degrade together alongside cellular reorganization. The aim of this study was to characterize this PCM‐degradation based on different cellular patterns. We additionally wanted to identify the earliest time point of PCM‐breakdown in this physiopathological model. To this end, cartilage samples were selected according to their predominant cellular pattern. Qualitative analysis of PCM degradation was performed immunohistochemically by analysing five main PCM components: collagen type VI, perlecan, collagen type III, biglycan, and fibrillin‐1 (n = 6 patients). Their protein content was quantified by enzyme‐linked immunosorbent assay (127 patients). Accompanying spatial cellular rearrangement, the PCM is progressively destroyed, with a pericellular signal loss in fluorescence microscopy for collagen type VI, perlecan, and biglycan. This loss in protein signal is accompanied by a reduction in total protein content from single strings to big clusters (P < .001 for collagen type VI, P = .003 for perlecan, and P < .001 for biglycan). As a result of an increase in the number of cells from single strings to big clusters, the amount of protein available per cell also decreases for collagen type III and fibrillin‐1, where total protein levels remain constant. Biochemical changes of the PCM and cellular rearrangement are thus highly interconnected hallmarks of osteoarthritis. Interestingly, the earliest point in time for a relevant PCM impairment appears to be at the transition to small clusters.

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Section: Discussionsupporting

confidence: 88%

Biochemical changes of the pericellular matrix and spatial chondrocyte organization—Two highly interconnected hallmarks of osteoarthritis

Danalache

Erler

Wolfgart

et al. 2020

Journal Orthopaedic Research

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“…BPG10 consists of a ∼10 kDa synthetic PAA core, decorated with ∼5−7 CS-GAG bristles (Figure 1a). The focus of BPG10 here was due to its capability of effectively diffusing into cartilage following intra-articular injection into rabbit knees in vivo 34 or after 24 h incubation of human or bovine explants in BPG10 aqueous solution in vitro. 35 Also, similar to aggrecan, BPG10 exhibits the "bottlebrush" architecture, with CS-GAGs packed at 3−4 nm spacing along the PAA core, 31 comparable to the 2−3 nm spacing of CS-GAGs along aggrecan core protein, 36 indicating that BPG10 may partially mimic the biophysical characteristics of native aggrecan.…”

Section: Resultsmentioning

confidence: 99%

Molecular Engineering of Pericellular Microniche via Biomimetic Proteoglycans Modulates Cell Mechanobiology

et al. 2022

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Molecular engineering of biological tissues using synthetic mimics of native matrix molecules can modulate the mechanical properties of the cellular microenvironment through physical interactions with existing matrix molecules, and in turn, mediate the corresponding cell mechanobiology. In articular cartilage, the pericellular matrix (PCM) is the immediate microniche that regulates cell fate, signaling, and metabolism. The negatively charged osmo-environment, as endowed by PCM proteoglycans, is a key biophysical cue for cell mechanosensing. This study demonstrated that biomimetic proteoglycans (BPGs), which mimic the ultrastructure and polyanionic nature of native proteoglycans, can be used to molecularly engineer PCM micromechanics and cell mechanotransduction in cartilage. Upon infiltration into bovine cartilage explant, we showed that localization of BPGs in the PCM leads to increased PCM micromodulus and enhanced chondrocyte intracellular calcium signaling. Applying molecular force spectroscopy, we revealed that BPGs integrate with native PCM through augmenting the molecular adhesion of aggrecan, the major PCM proteoglycan, at the nanoscale. These interactions are enabled by the biomimetic “bottle-brush” ultrastructure of BPGs and facilitate the integration of BPGs within the PCM. Thus, this class of biomimetic molecules can be used for modulating molecular interactions of pericellular proteoglycans and harnessing cell mechanosensing. Because the PCM is a prevalent feature of various cell types, BPGs hold promising potential for improving regeneration and disease modification for not only cartilage-related healthcare but many other tissues and diseases.

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“…We (Phillips et al, 2018;Prudnikova et al, 2017;Prudnikova et al, 2018;Sarkar, 2011;Sarkar et al, 2017;Sarkar, Lightfoot-Vidal, Schauer, Vresilovic, & Marcolongo, 2012) and others (Bernhard & Panitch, 2012;Place, Kelly, & Kipper, 2014;Sharma, Panitch, & Neu, 2013;Sharma, Vazquez-Portalatin, Calve, & Panitch, 2016) have been investigating mimics to proteoglycans. We designed, synthesized and characterized biomimetic proteoglycans (BPGs) that mimic the molecular architecture and physical properties of natural proteoglycans.…”

Section: Hartmannmentioning

confidence: 99%

“…In a previous study, fluorescently labeled BPGs were injected intra‐articularly in a rabbit knee joint in vivo model and BPG diffusion through cartilage was observed (Phillips et al, ). The intra‐articular injection of BPGs resulted in the diffusion of BPGs into and throughout the cartilage, localizing within the PCM.…”

Section: Introductionmentioning

confidence: 99%

Biomimetic proteoglycans diffuse throughout articular cartilage and localize within the pericellular matrix

Phillips

Haislup

Bertha

et al. 2019

J Biomedical Materials Res

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Biomimetic proteoglycan (BPG) diffusion into articular cartilage has the potential to restore the lost proteoglycan content in osteoarthritic cartilage given these molecules mimic the structure and properties of natural proteoglycans. We examined the diffusion characteristics of BPGs through cartilage with the use of a custom‐made in vitro cartilage diffusion model in both normal bovine and human osteoarthritic cartilage explants. BPGs were introduced into the cartilage through essentially one‐dimensional diffusion using osteochondral plugs. The molecular diffusion was shown to be size and concentration dependent. Diffusion profiles were found over different diffusion time intervals and the profiles were fit to a nonlinear Fickian diffusion model. Steady state 011012‐7diffusion coefficients for BPGs were found to be 4.01 and 3.53 μm2/s for 180 and 1600 kDa BPGs, respectfully, and these values are similar to other large molecule diffusion in cartilage. In both bovine and osteoarthritic human cartilage, BPGs were found localized around the chondrocytes. BPG localization was examined by labeling collagen type VI and soaking 5 μm thick sections of cartilage with BPG solutions demonstrating that the BPGs diffused into the cartilage and preferentially localized alongside collagen type VI in the pericellular matrix.

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Biomimetic proteoglycans can molecularly engineer early osteoarthritic cartilage in vivo

Cited by 15 publications

References 42 publications

Biochemical changes of the pericellular matrix and spatial chondrocyte organization—Two highly interconnected hallmarks of osteoarthritis

Biochemical changes of the pericellular matrix and spatial chondrocyte organization—Two highly interconnected hallmarks of osteoarthritis

Molecular Engineering of Pericellular Microniche via Biomimetic Proteoglycans Modulates Cell Mechanobiology

Biomimetic proteoglycans diffuse throughout articular cartilage and localize within the pericellular matrix

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