Incorporation of an aggrecan mimic prevents proteolytic degradation of anisotropic cartilage analogs

Sharma, Shikha; Panitch, Alyssa; Neu, Corey P.

doi:10.1016/j.actbio.2012.08.041

Cited by 48 publications

(58 citation statements)

References 54 publications

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“…It is speculated this inefficiency could have risen due to the fact that the combination treatment consists of twice the concentration of CS added since both mAGC and mAG(II)C were added. In our previous work with mAGC we noted the mimic’s ability to prevent collagen and HA degradation in tissue analogs as well as the ability to lower CS degradation from collagen analogs 21, 23 . These observations support the hypothesis that a biomimetic less susceptible to degradation prevents loss of ECM components.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we utilize bio-molecular ligands that bind to HA and collagen type II to design and deliver molecules that adhere to an aggrecan depleted cartilage matrix. The design, synthesis and characterization of several combinations of these molecules and their ability to resist in vitro proteolytic degradation has been previously described by our laboratory 21–23, 32 . We have also demonstrated the use of non-degradable nanoparticles to selectively deliver cell penetrating anti-inflammatory peptides to ‘inflamed’ cartilage explants 33 .…”

Section: Discussionmentioning

confidence: 99%

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Biomimetic Molecules Lower Catabolic Expression and Prevent Chondroitin Sulfate Degradation in an Osteoarthritic ex Vivo Model

Sharma

Vazquez-Portalatin

Calve

et al. 2016

ACS Biomater. Sci. Eng.

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Aggrecan, the major proteoglycan in cartilage, serves to protect cartilage tissue from damage and degradation during the progression of osteoarthritis (OA). In cartilage extracellular matrix (ECM) aggrecan exists in an aggregate composed of several aggrecan molecules that bind to a single filament of hyaluronan. Each molecule of aggrecan is composed of a protein core and glycosaminoglycan sides chains, the latter of which provides cartilage with the ability to retain water and resist compressive loads. During the progression of OA, loss of aggrecan is considered to occur first, after which other cartilage matrix components become extremely susceptible to degradation. Proteolytic cleavage of the protein core of aggrecan by enzymes such as aggrecanases, prevent its binding to HA and lower cartilage mechanical strength. Here we present the use of HA-binding or collagen type II-binding molecules that functionally mimic aggrecan but lack known cleavage sites, protecting the molecule from proteolytic degradation. These molecules synthesized with chondroitin sulfate backbones conjugated to hyaluronan-or collagen type IIbinding peptides, are capable of diffusing through a cartilage explant and adhering to the ECM of this tissue. The objective of this study was to test the functional efficacy of these molecules in an ex vivo osteoarthritic model to discern the optimal molecule for further studies. Different variations of chondroitin sulfate conjugated to the binding peptides were diffused through aggrecan depleted explants and assessed for their ability to enhance compressive stiffness, prevent CS degradation, and modulate catabolic (MMP-13 and ADAMTS-5) and anabolic (aggrecan and collagen type II) gene expression. A pilot in vivo study assessed the ability to retain the molecule within the joint space of an osteoarthritic guinea pig model. The results indicate chondroitin sulfate conjugated to hyaluronan-binding peptides is able to significantly restore equilibrium modulus and prevent CS degradation. All molecules demonstrated the ability to lower catabolic gene expression in aggrecan depleted explants. In order to enhance biosynthesis and regeneration, the molecules need to be coupled with an external stimulant such as a growth factor. The chondroitin sulfate molecule synthesized with HA-binding peptides demonstrated adherence to

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Biomimetic Molecules Lower Catabolic Expression and Prevent Chondroitin Sulfate Degradation in an Osteoarthritic ex Vivo Model

Sharma

Vazquez-Portalatin

Calve

et al. 2016

ACS Biomater. Sci. Eng.

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“…This peptidoglycan aggrecan mimetic (mAGC) containing CS chains with attached HABPs replicated the HA-binding properties of native aggrecan ensuring that GAG localization was maintained within the scaffold. [204] mAGC had superior water regain properties to that of native aggrecan and mAGC constructs had superior compressive strength (78% increase), The catabolism of mAGC constructs by MMP-13 and ADAMTS-5 [206,207] was also reduced compared to in animal models of OA. AFM demonstrated that the attached peptide chains in mAGC assumed bottle-brush-type orientations on the CS-core structure similar to the CS chain arrangements in native aggrecan core protein.…”

Section: Production Of Biomimetic Neo-aggrecanmentioning

confidence: 96%

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

Hayes

Melrose

2019

Advanced Therapeutics

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The aim of this study is to review developments in glycosaminoglycan and proteoglycan research relevant to cartilage repair biology and in particular the treatment of osteoarthritis (OA). Glycosaminoglycans decorate a diverse range of extracellular matrix and cell associated proteoglycans conveying structural organization and physico-chemical properties to tissues. They play key roles mediating cellular interactions with bioactive growth factors, cytokines, and morphogenetic proteins, and structural fibrillar collagens, cell interactive and extracellular matrix proteoglycans, and glycoproteins which define tissue function. Proteoglycan degradation detrimentally affects tissue functional properties. Therapeutic strategies have been developed to counter these degenerative changes. Neo-proteoglycans prepared from chondroitin sulfate or hyaluronan and hyaluronan or collagen-binding peptides emulate the interactive, water imbibing, weight bearing, and surface lubricative properties of native proteoglycans. Many neo-proteoglycans outperform native proteoglycans in terms of water imbibition, matrix stabilization, and resistance to proteolytic degradation. The biospecificity of recombinant proteoglycans however, provides precise attachment to native target molecules. Visco-supplements augmented with growth factors/therapeutic cells, hyaluronan, and lubricin (orthobiologicals) have the capacity to lubricate and protect cartilage, control inflammation, and promote cartilage repair and regeneration of early cartilage lesions and may represent a more effective therapeutic approach to the treatment of mild to moderate OA and deserve further study.Similar protective perineural net structures assembled from the lectican proteoglycan family and HA also occur in the CNS/PNS. These so called perineuronal nets are visualized by immunolocalization of MAb 1B5 (+) epitope in rat brain (e) and pericellular 1B5(+) epitope expression by isolated neurons (f). Scale bars 100 µm.

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“…While the influence of the interstitial ECM on cartilage mechanics, e.g. aggrecan and type II collagen, has been extensively studied at the tissue scale (Buschmann et al, 1999; Darling et al, 2004; Sharma et al, 2013), only recently has attention been focused towards the biomechanical measurement of the PCM with the adoption of atomic force microscopy (AFM) as a testing modality (Alexopoulos et al, 2009; Wilusz et al, 2012). AFM is the primary methodology utilized to resolve differences in mechanical properties at the cellular level; however, the geometry and heterogeneity of most tissues precludes the testing of intact specimens.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of the pericellular matrix molecule perlecan lowers in situ cell and matrix stiffness in developing cartilage

Leng

et al. 2016

Developmental Biology

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The pericellular matrix (PCM) is a component of the extracellular matrix that is found immediately surrounding individual chondrocytes in developing and adult cartilage, and is rich in the proteoglycan perlecan. Mutations in perlecan are the basis of several developmental disorders, which are thought to arise from disruptions in the mechanical stability of the PCM. We tested the hypothesis that defects in PCM organization will reduce the stiffness of chondrocytes in developing cartilage by combining a murine model of Schwartz-Jampel syndrome, in which perlecan is knocked down, with our novel atomic force microscopy technique that can measure the stiffness of living cells and surrounding matrix in embryonic and postnatal tissues in situ. Perlecan knockdown altered matrix organization and significantly decreased the stiffness of both chondrocytes and interstitial matrix as a function of age and genotype. Our results demonstrate that the knockdown of a spatially restricted matrix molecule can have a profound influence on cell and tissue stiffness, implicating a role for outside-in mechanical signals from the PCM in regulating the intracellular mechanisms required for the overall development of cartilage.

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Incorporation of an aggrecan mimic prevents proteolytic degradation of anisotropic cartilage analogs

Cited by 48 publications

References 54 publications

Biomimetic Molecules Lower Catabolic Expression and Prevent Chondroitin Sulfate Degradation in an Osteoarthritic ex Vivo Model

Biomimetic Molecules Lower Catabolic Expression and Prevent Chondroitin Sulfate Degradation in an Osteoarthritic ex Vivo Model

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

Knockdown of the pericellular matrix molecule perlecan lowers in situ cell and matrix stiffness in developing cartilage

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