Preserving the longevity of long-lived type II collagen and its implication for cartilage therapeutics (original) (raw)
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Polymerized-Type I Collagen Induces a High Quality Cartilage Repair in a Rat Model of Osteoarthritis
International Journal of Bone and Rheumatology Research
Background: Osteoarthritis (OA) is a chronic, degenerative and inflammatory disease. It is characterized by progressive deterioration of articular cartilage. It is the most common disabling rheumatic pathology in adults older than 45 years, and there is no specific treatment. Objectives: Based on the rationale that in vitro polymerized-type I collagen induces chondrocytes proliferation, up-regulates the cartilage extracellular matrix proteins and down-regulates proinflammatory cytokines, we decided to evaluate its effect on cartilage repair in a rat model of OA. Methods: Thirty Wistar male rats with partial meniscectomy were subjected to daily high impact exercise during 3 weeks. Rats were randomly allocated into 5 groups a) training control, b)sham/operated control, c) toxicity control, d) OA treated with 4 intraarticular (IA) injections of placebo, and e) OA treated with 4 IA injections of polymerized-type I collagen. Weight, temperature and thickness of the knee were measured. Histological and radiological analysis was also performed. Type I and II collagen as well as, MMP13 expression was determined by immunofluorescence. Results: Clinimorphometric analysis showed a higher temperature and thickness of the knee in OA/placebo vs. OA/polymerized-type I collagen treated rats. Radiological and histological analysis demonstrated that polymerized-type I collagen but not placebo preserved joint cavity structure and proteoglycans content and induced an increase of 2 to 4 fold type II collagenexpressing chondrocytes whereas it inhibited type I collagen and MMP13 producing chondrocytes. Conclusion: The results suggest that polymerized-type I collagen is safe and effective chondroprotective biodrug with disease modifying effects. It induces high quality cartilage repair.
Arthritic diseases, such as osteoarthritis and rheumatoid arthritis, inflict an enormous health care burden on society. Osteoarthritis, a degenerative joint disease with high prevalence among older people, and rheumatoid arthritis, an autoimmune inflammatory disease, both lead to irreversible structural and functional damage to articular cartilage. The aim of this study was to investigate the effect of polyphenols such as catechin, quercetin, epigallocatechin gallate, and tannic acid, on crosslinking type II collagen and the roles of these agents in managing in vivo articular cartilage degradation. The thermal, enzymatic, and physical stability of bovine articular cartilage explants following polyphenolic treatment were assessed for efficiency. Epigallocatechin gallate and tannic acid-treated explants showed >12°C increase over native cartilage in thermal stability, thereby confirming cartilage crosslinking. Polyphenol-treated cartilage also showed a significant reduction in the percentage of collagen degradation and the release of glycosaminoglycans against collagenase digestion, indicating the increase physical integrity and resistance of polyphenol crosslinked cartilage to enzymatic digestion. To examine the in vivo cartilage protective effects, polyphenols were injected intra-articularly before (prophylactic) and after (therapeutic) the induction of collagen-induced arthritis in rats. The hind paw volume and histomorphological scoring was done for cartilage damage. The intra-articular injection of epigallocatechin gallate and tannic acid did not significantly influence the time of onset or the intensity of joint inflammation. However, histomorphological scoring of the articular cartilage showed a significant reduction in cartilage degradation in prophylactic-and therapeutic-groups, indicating that intraarticular injections of polyphenols bind to articular cartilage and making it resistant to degradation despite ongoing inflammation. These studies establish the value of intra-articular injections of polyphenol in stabilization of cartilage collagen against degradation and indicate PLOS ONE |
Arthritis & Rheumatism, 2002
Objective. Age is an important risk factor for osteoarthritis (OA). During aging, nonenzymatic glycation results in the accumulation of advanced glycation end products (AGEs) in cartilage collagen. We studied the effect of AGE crosslinking on the stiffness of the collagen network in human articular cartilage. Methods. To increase AGE levels, human adult articular cartilage was incubated with threose. The stiffness of the collagen network was measured as the instantaneous deformation (ID) of the cartilage and as the change in tensile stress in the collagen network as a function of hydration (osmotic stress technique). AGE levels in the collagen network were determined as: N-(carboxy[m]ethyl)lysine, pentosidine, amino acid modification (loss of arginine and [hydroxy-]lysine), AGE fluorescence (360/460 nm), and digestibility by bacterial collagenase. Results. Incubation of cartilage with threose resulted in a dose-dependent increase in AGEs and a concomitant decrease in ID (r ؍ ؊0.81, P < 0.001; up to a 40% decrease at 200 mM threose), i.e., increased stiffness, which was confirmed by results from the osmotic stress technique. The decreased ID strongly correlated with AGE levels (e.g., AGE fluorescence r ؍ ؊0.81, P < 0.0001). Coincubation with arginine or lysine (glycation inhibitors) attenuated the threoseinduced decrease in ID (P < 0.05). Conclusion. Increasing cartilage AGE crosslinking by in vitro incubation with threose resulted in increased stiffness of the collagen network. Increased stiffness by AGE crosslinking may contribute to the age-related failure of the collagen network in human articular cartilage to resist damage. Thus, the agerelated accumulation of AGE crosslinks presents a putative molecular mechanism whereby age is a predisposing factor for the development of OA. Osteoarthritis (OA) is a common chronic disabling disorder for which age is the single greatest risk factor (1,2). Although age-related changes in articular cartilage are likely to play a role, the mechanism by which age increases the susceptibility to joint degeneration is largely unknown. Swelling of cartilage, which is proportional to the amount of damaged collagen (3), is the initial event in cartilage degeneration (4), indicating
A Novel Approach to Stimulate Cartilage Repair: Targeting Collagen Turnover
OA is a complex disease of which the ethiopathology is not completely known and therapies to repair cartilage are still under investigation. The increase of collagen type II expression in osteoarthritic cartilage suggests an activated repair mechanism that is however ineffective in repairing or maintaining the ECM homeostasis. We therefore investigated the ability to modulate the formation of a functional collagen type II network that can ultimately contribute to innovation of cartilage repair in OA. To do so we used different approaches: addition of growth factors, inhibition of collagen cross-links, inhibition of proteoglycan formation, overexpression of cartilage oligomeric matrix protein (COMP) and knock-down of COMP and collagen IX, Of the growth factors used in this thesis, IGF1 had positive effects on the parameters in our chondrocyte alginate cultures. It stimulated chondrocytes to deposit more collagen and proteoglycans without affecting collagen cross-linking, it increased...
Biomaterials, 2002
The limited intrinsic repair capacity of articular cartilage has stimulated continuing efforts to develop tissue engineered analogues. Matrices composed of type II collagen and chondroitin sulfate (CS), the major constituents of hyaline cartilage, may create an appropriate environment for the generation of cartilage-like tissue. In this study, we prepared, characterized, and evaluated type II collagen matrices with and without CS. Type II collagen matrices were prepared using purified, pepsin-treated, type II collagen. Techniques applied to prepare type I collagen matrices were found unsuitable for type II collagen. Crosslinking of collagen and covalent attachment of CS was performed using 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide. Porous matrices were prepared by freezing and lyophilization, and their physico-chemical characteristics (degree of crosslinking, denaturing temperature, collagenase-resistance, amount of CS incorporated) established. Matrices were evaluated for their capacity to sustain chondrocyte proliferation and differentiation in vitro. After 7 d of culture, chondrocytes were mainly located at the periphery of the matrices. In contrast to type I collagen, type II collagen supported the distribution of cells throughout the matrix. After 14 d of culture, matrices were surfaced with a cartilagenous-like layer, and occasionally clusters of chondrocytes were present inside the matrix. Chondrocytes proliferated and differentiated as indicated by biochemical analyses, ultrastructural observations, and reverse transcriptase PCR for collagen types I, II and X. No major differences were observed with respect to the presence or absence of CS in the matrices. r
Frontiers in Veterinary Science, 2021
Osteoarthritis (OA) is an age-related joint disease that includes gradual disruption of the articular cartilage and the resulting pain. The present study was designed to test the effects of undenatured type II collagen (UC-II ®) on joint inflammation in the monoiodoacetate (MIA) OA model. We also investigated possible mechanisms underlying these effects. Female Wistar rats were divided into three groups: (i) Control; (ii) MIA-induced rats treated with vehicle; (iii) MIA-induced rats treated with UC-II (4 mg/kg BW). OA was induced in rats by intra-articular injection of MIA (1 mg) after seven days of UC-II treatment. UC-II reduced MIA-induced Kellgren-Lawrence scoring (53.3%, P < 0.05). The serum levels of inflammatory cytokines [IL-1β (7.8%), IL-6 (18.0%), TNF-α (25.9%), COMP (16.4%), CRP (32.4%)] were reduced in UC-II supplemented group (P < 0.0001). In the articular cartilage, UC-II inhibited the production of PGE2 (19.6%) and the expression of IL-1β, IL-6, TNF-a, COX-2, MCP-1, NF-κB, MMP-3, RANKL (P < 0.001). The COL-1 and OPG levels were increased, and MDA decreased in UC-II supplemented rats (P < 0.001). UC-II could be useful to alleviate joint inflammation and pain in OA joints by reducing the expression of inflammatory mediators.
Protein-based injectable hydrogels towards the regeneration of articular cartilage
2000
Articular cartilage is a tissue with low capacity for self-restoration due to its avascularity and low cell population. It is located on the surface of the subchondral bone covering the diarthrodial joints. Degeneration of articular cartilage can appear in athletes, in people with genetic degenerative processes (osteoarthritis or rheumatoid arthritis) or due to a trauma; what produces pain, difficulties in mobility and progressive degeneration that finally leads to joint failure. Self-restoration is only produced when the defect reaches the subchondral bone and bone marrow mesenchymal stem cells (MSCs) invade the defect. However, this new formed tissue is a fibrocartilaginous type cartilage and not a hyaline cartilage, which finally leads to degeneration. Transplantation of autologous chondrocytes has been proposed to regenerate articular cartilage but this therapy fails mainly due to the absence of a material support (scaffold) for the adequate stimulation of cells. Matrix-induced autologous chondrocyte implantation uses a collagen hydrogel as scaffold for chondrocytes; however, it does not have the adequate mechanical properties, does not provide the biological cues for cells and regenerated tissue is not articular cartilage but fibrocartilage. Different approaches have been done until now in order to obtain a scaffold that better mimics articular cartilage properties and composition. Hydrogels are a good option as they retain high amounts of water, in a similar way to the natural tissue, and can closely mimic the composition of natural tissue by the combination of natural derived hydrogels. Their three-dimensionality plays a critical role in articular cartilage tissue engineering to maintain chondrocyte function, since monolayer culture of chondrocytes makes them dedifferentiate towards a fibroblast-like phenotype secreting fibrocartilage. Recently, injectable hydrogels have attracted attention for the tissue engineering of articular cartilage due to their ability to encapsulate cells, injectability in the injury with minimal invasive surgeries and Abstract adaptability to the shape of the defect. Following this new approach we aimed at synthesizing two new families of injectable hydrogels based on the natural protein gelatin for the tissue engineering of articular cartilage. The first series of materials consisted on the combination of injectable gelatin with loose reinforcing polymeric microfibers to obtain injectable composites with improved mechanical properties. Our results demonstrate that there is an influence of the shape and distribution of the fibers in the mechanical properties of the composite. More importantly bad fiber-matrix interaction is not able to reinforce the hydrogel. Due to this, our composites were optimized by improving matrix-fiber interaction through a hydrophilic grafting onto the microfibers, with very successful results. L´última part d´aquesta tesi és dedicada a la síntesi d´un material no biodegradable amb propietats mecàniques, inflat i permeabilitat similar al cartílag. Aquest material pretén ser utilitzat com a plataforma a un bioreactor que simula les cargues típiques de les articulacions, de manera que els hidrogels o scaffolds encaixarien als buits de la plataforma. La funció de la plataforma és simular l´efecte del teixit circumdant al scaffold després de la seua implantació i podria reduir l'experimentació animal mitjançant la simulació de les condicions in vivo. 1.1.1. Tissue organization Articular cartilage can be considered a complex multiphasic tissue with both fluid and solid phases. The fluid phase is composed of water and dissolved electrolytes (60-85% of wet weight), and the solid phase is formed by the extracellular matrix (ECM), which has collagen (10-30% of the wet weight), proteoglycans (3-10% of wet weight) and some glycoproteins and lipids [4]. Type II collagen forms 90% of the macrofibrillar collagen network [4]. This collagen is in the form of fibrils composed of three α 1 (II) chains, forming a triple helix with amino and carboxyl groups at each end. Intra and intermolecular bonds are formed between the lysine residues present in the collagen chains to compose the fibril. Type IX collagen represents 2% of the collagen fibril and is located on its surface in an antiparallel direction (see Figure 1-1). Collagen Type XI is also present within the fibril and on its surface, and its main functions are fibril self-assembly and limiting its lateral growth. The proteoglycan decorin is bonded to the collagen fibril, reducing its final diameter [2]. The percentage of collagen decreases with distance from the articular surface [5]. Proteoglycans and Type II collagen are some of the principal components of articular cartilage. Proteoglycan concentration varies inversely with collagen content. Lower concentrations of
Contribution of collagen network features to functional properties of engineered cartilage
Osteoarthritis and Cartilage, 2008
Background: Damage to articular cartilage is one of the features of osteoarthritis (OA). Cartilage damage is characterised by a net loss of collagen and proteoglycans. The collagen network is considered highly important for cartilage function but little is known about processes that control composition and function of the cartilage collagen network in cartilage tissue engineering. Therefore, our aim was to study the contribution of collagen amount and number of crosslinks on the functionality of newly formed matrix during cartilage repair.