Protection Of Articular Cartilage Research Articles

Stem Cell Administration to Repair Torn Menisci

The meniscus is a crescent-shaped, fibrocartilaginous padding in the knee that contains variable vascularization and histology. This structure enables proper loadbearing, knee movement, and protection of articular cartilage and bone of the tibiofemoral joint. The meniscus is subject to tears from acute injury and degenerative stresses. Many meniscal tears do not heal naturally due to poor vascularization and high stresses placed on the meniscus. These often result in pain and mechanical symptoms and are highly correlated to osteoarthritis (OA) development. While there are a wide variety of suggested treatments for meniscal tears, studies indicate common surgical interventions have little to no significant improvements in abating patient symptoms or limiting osteoarthritic progression, with high failure rates. Therefore, alternative treatments are being actively explored for meniscal tear repair. One of the most-researched treatment options is using mesenchymal stem cells (MSC), a type of adult multilineage progenitor cell capable of facilitating meniscal tissue regeneration. Many different types of MSCs and supplemental, cuttingedge techniques are being tested to maximize tear healing. MSCs hold great promise for regenerating meniscal tissue, limiting OA, and restoring joint functionality. However, more research is required to prove the significance of stem cell treatments in humans and define the conditions for their use.

A current insight into Human Knee Menisci

Menisci of the knee are semilunar-shaped structures located between the condyles of the femur and tibia, together with articular surfaces of the tibial condyles form the acetabulum of the knee joint. They have multiple functions, affecting the proper joint biomechanics, even though in the past they were perceived as embryonic remnants. Menisci are involved in such vital functions as: load bearing, joint stability, joint congruity, increasing joint contact area, decreasing joint contact stresses, protection of articular cartilage, shock absorption, lubrication, limitation of extreme movement and proprioception.Menisci arise from a condensation of the intermediate layer of mesenchymal tissue. At later stages of development, it is observed a gradual decrease in the cellularity of the structure and increase of the collagen fibers, where collagen type I is a major fibrillar component. The meniscus is composed of an extracellular matrix mainly filled with water (72%) and collagen (22%), with a minority of proteoglycans, glycoproteins, peptides, and local cells - fibrochondrocytes.When it comes to vascularization, two main areas are present in the structure of meniscus: red-red zone - vascular, white-white zone – rather avascular, and in between the red-white zone. Major vascularization is ensured by the popliteal artery branches: medial, lateral and middle geniculate arteries. It was shown that meniscus can be vascularized in each zone, what is linked with the hypovascular zone regenerative potential. The vascularization pattern and nutritional status of a torn meniscus and the morphological pattern of the tear are crucial factors determining the success of a meniscus surgery. The healing potential of a torn meniscus is directly dependent on its blood supply.At present, it is known that proper performance of the knee joint is directly proportional to the amount of meniscus tissue. Their involvement in the multiple important functions leads to modern solutions focused on saving meniscus tissue.

Advances in 3D Bioprinting of Biomimetic and Engineered Meniscal Grafts.

The meniscus plays a crucial role in loads distribution and protection of articular cartilage. Meniscal injury can result in cartilage degeneration, loss of mechanical stability in the knee joint and ultimately lead to arthritis. Surgical interventions provide only short-term pain relief but fail to repair or regenerate the injured meniscus. Emerging tissue engineering approaches based on 3D bioprinting provide alternatives to current surgical methods for meniscus repair. In this review, we summarize the current bioprinting techniques employed in developing engineered meniscus grafts and discuss the latest strategies for mimicking the gradient structure, composition and viscoelastic properties of native meniscus. We highlight recent progress in gene-activated matrices for meniscus regeneration as well. Finally, we provide a perspective on the future development of 3D bioprinting for meniscus repair, emphasizing the potential of this technology to revolutionize meniscus regeneration and improve patient outcomes. This article is protected by copyright. All rights reserved.

Catalytic anti-oxidative stress for osteoarthritis treatment by few-layered phosphorene.

As one of the most common representations of articular cartilage damage, osteoarthritis (OA) is characterized by the apoptosis and dysfunction of chondrocytes as well as the progressive degradation of extracellular matrix, of which the main components are glycosaminoglycan and type Ⅱ collagen. Few-layered phosphorene (FLP) has been attracting great attentions in biomedical fields owing to the excellent capability of in-situ catalysis for scavenging oxidate-associated molecules, especially the reactive oxygen species (ROS) and reactive nitrogen species (RNS). Herein, FLP has been fabricated and employed for articular cartilage protection by means of deleting oxidate-associated molecules. The in vitro results show that as low as 200​μg/mL FLP is capable of diminishing oxidative damages on the osteoarthritic chondrocytes through the efficient elimination of ROS, H2O2 and NO. Meanwhile, the cartilage matrix protection has also been achieved at 200​μg/mL FLP by the uniform restoration of glycosaminoglycan and type Ⅱ collagen. FLP enables the nanocatalytic treatment for the overloaded oxidative stress in the injured articular cartilage and represents a promising alternative for osteoarthritis therapy.

Lateral meniscus allograft transplantation without bone plugs: technique and outcomes.

Once considered a non-fundamental structure, the menisci are now known to provide several functions within the knee, including protection of articular cartilage, load-bearing, shock absorption, joint stability, joint lubrification and joint congruity functions. Meniscal tears are one of the most common lesions in knee orthopedics, and partial or total meniscectomies are commonly performed procedures in orthopedic surgery. Despite meniscectomy is well recognized to lead improvement in clinical outcomes, it has been related to early onset knee osteoarthritis and joint degeneration which are associated with pain and functional limitations. Meniscal allograft transplantation has become a viable option for patients under 55 years old that have undergone total or near total meniscectomy and are in a painful state. This procedure can be performed using bone plugs or without bone plugs. In the bone plugs free technique allograft will be presented as a lateral meniscus with a portion of tibial plateau and is then introduced into the joint through an arthroscopic portal and fixed to the capsule with all-inside stitches. The most important aspect required to obtain good clinical results are graft size, anatomic placement and fixation, because extrusion is the most common complication related to meniscal transplantation. Although a lack of long-term follow-up (FU) studies, it has been demonstrated that lateral meniscus transplantation without bone plugs is a minimal invasive surgical procedure that improves the knee function, increases patient physical activity and reduces pain.

Efficacy Treatment of Osteoarthritis with Combine Chondroitin and Glucosamine.

Osteoarthritis led to the articular cartilage damage and cause different kind of problems - from social to biological. The analysis of existing research unfortunately subjected questioned the reliability of spontaneous regeneration of damaged cartilage, which makes it necessary to focus on the possibilities of protection of the tissue from further its degradation. Treatment of osteoarthritis require to use many drugs, which would lead to slowdown the this process. The aim of below publication is to analyse the practical, clinical biological possibilities of articular cartilage protection with a usage of SYSADOA - (symptomatic slow acting drugs of OA). Osteoarthritis is most frequent disease of the joints and prescription of the SYSADOA should be main principle of that treatment.

Preclinical Characterization of the Selective JAK1 Inhibitor LW402 for Treatment of Rheumatoid Arthritis.

BackgroundResearch on JAK family members as therapeutic targets for autoimmune diseases has brought tofacitinib and baricitinib into clinical for the treatment of rheumatoid arthritis and other autoimmune diseases. Despite the potent efficacy of these first-generation JAK inhibitors, their broad-spectrum JAK inhibition and adverse events warrant development of a JAK1-specific inhibitor to improve their safety profile.MethodsIn this study, we characterized a JAK1-specific inhibitor, LW402, on biochemical and human whole-blood assays. We further evaluated the therapeutic efficacy of LW402 in a rat adjuvant-induced arthritis (rAIA) model and a mouse collagen-induced arthritis (mCIA) model. The safety of LW402 was evaluated in both SpragueDawley rats and cynomolgus monkeys.ResultsLW402 exhibited potent nanomolar activity against JAK1 and showed a 45-fold selectivity for inhibition of JAK1- over JAK2-dependent signaling induced by either IL6 or GM-CSF in human whole-blood assays. In the rAIA model, oral dosing of LW402 resulted in a dose-dependent improvement in disease symptoms, including reduction in paw swelling, marked reduction in the inflammatory-cell infiltration to synovial tissue, and protection of articular cartilage and bone from damage. The therapeutic efficacy of LW402 correlated well with the plasma exposure of LW402 and the extent of pSTAT3 inhibition in white blood cells. LW402 also effectively eased disease symptoms in the mCIA model. Toxicity studies in the Sprague Dawley rats and cynomolgus monkeys established a ≥5x therapeutic window for LW402 as drug exposures of toxicity study NOAEL dose and pharmacology study ED50 dose were compared.ConclusionWe developed a novel JAK1-specific inhibitor LW402 with potent efficacy in rAIA and mCIA models. We established a good safety profile for LW402 in toxicity studies, and the overall superiority of LW402 should translated well to the clinical setting for the treatment of RA and other autoimmune diseases.

Characterization and Comparison of Postnatal Rat Meniscus Stem Cells at Different Developmental Stages.

Meniscus‐derived stem cells (MeSCs) are a potential cell source for meniscus tissue engineering. The stark morphological and structural changes of meniscus tissue during development indicate the complexity of MeSCs at different tissue regions and stages of development. In this study, we characterized and compared postnatal rat meniscus tissue and MeSCs at different tissue regions and stages of development. We observed that the rat meniscus tissue exhibited marked changes in tissue morphology during development, with day 7 being the most representative time point of different developmental stages. All rat MeSCs displayed typical stem cell characteristics. Rat MeSCs derived from day 7 inner meniscus tissue exhibited the highest self‐renewal capacity, cell proliferation, differentiation potential toward various mesenchymal lineage and the highest expression levels of chondrogenic genes and proteins. Transplantation of rat MeSCs derived from day 7 inner meniscus tissue promoted neo‐tissue formation and effectively protected joint surface cartilage in vivo. Our results demonstrated for the first time that rat MeSCs are not necessarily better at earlier developmental stages, and that rat MeSCs derived from day 7 inner meniscus tissue may be a superior cell source for effective meniscus regeneration and articular cartilage protection. This information could make a significant contribution to human meniscus tissue engineering in the future. stem cells translational medicine 2019;8:1318&1329

Mid-term effectiveness of arthroscopic anterior cruciate ligament reconstruction combined with meniscus allograft transplantation

To summarize the mid-term effectiveness of arthroscopic anterior cruciate ligament (ACL) reconstruction combined with meniscus allograft transplantation. A clinical data of 21 patients treated with arthroscopic ACL reconstruction and meniscus allograft transplantation and followed up more than 5 years between February 2007 and December 2014 was retrospectively analyzed. There were 12 males and 9 females, aged from 18 to 45 years, with an average age of 23.5 years. The cause of injury was sport sprain in 15 cases, falling in 4 cases, and traffic accident in 2 cases. The time from injury to operation ranged from 2 to 36 months, with an average of 12 months. Among them, 15 patients underwent previous meniscectomy, with an average interval of 1.6 years (range, 3 months to 6.5 years). All patients were primary ACL reconstruction. Preoperative anterior drawer test, Lachman test, and pivot shift test were positive. Lysholm score was 43.6±10.2. International Knee Documentation Committee (IKDC) score was 60.50±14.06. Of the 21 patients, 10 were gradeⅠ-Ⅱcartilage injuries and 11 were grade Ⅲ cartilage injuries according to MRI. All patients were followed up 5.1-7.8 years, with an average of 5.5 years. There were 2 cases of numbness of lower extremity, 3 cases of slight exudation of incision, 2 cases of articular movement bounce, 5 cases of mild joint swelling and pain after exercise. At last follow-up, Lachman tests were negative in 18 cases and positive in 3 cases; anterior drawer tests were negative in 19 cases and positive in 2 cases; pivot shift tests were negative in all cases. Lysholm score was 84.5±16.5 and IKDC score was 85.25±4.60, which were significantly higher than those before operation ( P<0.01). The flexion and extension of the affected knee joint were (128±13) and (3±7)°, respectively, which were smaller than those of the healthy knee joint [(133±15), (0±5)°] ( P<0.01). The results of KT-1000 test showed that when knee flexion was 30 and 90°, tibial anterior displacement of affected side [(2.35±1.20), (1.60±1.15) mm] were not significantly different from those of healthy side [(1.20±1.10), (1.10±1.03) mm] ( P>0.01). MRI showed that the ACL graft was in normal position and meniscus survived well. Cartilage injuries were gradeⅠ-Ⅱ in 18 cases and grade Ⅲ in 3 cases. For patients with severe meniscus injury and ACL rupture, ACL reconstruction combined with meniscus allograft transplantation can restore the stability of the joint, recover the meniscus function which is conducive to the protection of articular cartilage and obtain satisfactory mid-term effectiveness.

First Clinical Application of Polyurethane Meniscal Scaffolds with Mesenchymal Stem Cells and Assessment of Cartilage Quality with T2 Mapping at 12 Months.

Complex meniscal lesions often require meniscectomy with favorable results in the short term but a high risk of early osteoarthritis subsequently. Partial meniscectomy treated with meniscal substitutes may delay articular cartilage degeneration. To evaluate the status of articular cartilage by T2 mapping after meniscal substitution with polyurethane scaffolds enriched with mesenchymal stem cells (MSC) and comparison with acellular scaffolds at 12 months. Seventeen patients (18-50 years) with past meniscectomies were enrolled in 2 groups: (1) acellular polyurethane scaffold (APS) or (2) polyurethane scaffold enriched with MSC (MPS). Patients in the MPS group received filgrastim to stimulate MSC production, and CD90+ cells were obtained and cultured in the polyurethane scaffold. The scaffolds were implanted arthroscopically into partial meniscus defects. Concomitant injuries (articular cartilage lesions or cartilage lesions) were treated during the same procedure. Changes in the quality of articular cartilage were evaluated with T2 mapping in femur and tibia at 12 months. In tibial T2 mapping, values for the MPS group increased slightly at 9 months but returned to initial values at 12 months (P > 0.05). In the APS group, a clear decrease from 3 months to 12 months was observed (P > 0.05). This difference tended to be significantly lower in the APS group compared with the MPS group at the final time point (P = 0.18). In the femur, a slight increase in the MPS group (47.8 ± 3.4) compared with the APS group (45.3 ± 4.9) was observed (P > 0.05). Meniscal substitution with polyurethane scaffold maintains normal T2 mapping values in adjacent cartilage at 12 months. The addition of MSC did not show any advantage in the protection of articular cartilage over acellular scaffolds (P > 0.05).

Long-term Evaluation of Meniscal Tissue Formation in 3-dimensional–Printed Scaffolds With Sequential Release of Connective Tissue Growth Factor and TGF-β3 in an Ovine Model

Background: Artificial meniscal scaffolds are being developed to prevent development of osteoarthritis after meniscectomy. Previously, it was reported that 3-dimensional (3D) anatomic scaffolds loaded with connective tissue growth factor (CTGF) and transforming growth factor β3 (TGF-β3) achieved meniscal regeneration in an ovine model. This was a relatively short-term study (3 months postoperative), and outcome analyses did not include magnetic resonance imaging (MRI). Purpose: To evaluate long-term outcome of meniscal replacement with growth factor–laden poly-ε-caprolactone (PCL) scaffolds. Study Design: Controlled laboratory study. Methods: Anatomically shaped ovine meniscal scaffolds were fabricated from PCL with a 3D printer based on MRI data. Skeletally mature sheep (N = 34) were randomly allocated to 3 groups: scaffold without growth factor (0-µg group), scaffold with CTGF microspheres (µS) (5 µg) + TGF-β3 µS (5 µg) (5-µg group), and scaffold with CTGF µS (10 µg) + TGF-β3 µS (10 µg) (10-µg group). Unilateral medial meniscal replacement was performed. Animals were euthanized at 6 or 12 months. Regenerated meniscus, articular cartilage status, and synovial reaction were evaluated quantitatively with gross inspection, histology, and MRI. Kruskal-Wallis and Dunn tests were used to compare the 3 groups. Results: Remnants of the PCL scaffold were evident in the 6-month specimens and were decreased but still present at 12 months in most animals. There were no significant differences among groups in gross inspection, histology, or MRI for either meniscal regeneration or articular cartilage protection. All experimental groups exhibited articular cartilage degeneration as compared with control (nonoperated). In terms of synovitis, there were no clear differences among groups, suggesting that growth factors did not increase inflammation and fibrosis. MRI revealed that meniscal extrusion was observed in most animals (82.7%). Conclusion: Previously, the combination of CTGF and TGF-β3 was shown to stimulate mesenchymal stem cells into a fibrochondrocyte lineage. CTGF and TGF-β3 did not aggravate synovitis, suggesting no adverse response to the combination of 3D-printed PCL scaffold combined with CTGF and TGF-β3. Further work will be required to improve scaffold fixation to avoid meniscal extrusion. Clinical Relevance: A significant advantage of this technique is the ability to print custom-fit scaffolds from MRI-generated templates. In addition, average-size menisci could be printed and available for off-the-shelf applications. Based on the 1-year duration of the study, the approach appears to be promising for meniscal regeneration in humans.

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

AbstractThe 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.

Articular cartilage protection in Ctsk-/- mice is associated with cellular and molecular changes in subchondral bone and cartilage matrix.

Osteoarthritis (OA) is a degenerative disease and a major cause of chronic disability in aging individuals. Cathepsin K (CatK), encoded by the Ctsk gene, has been implicated in the pathogenesis of pycnodysostosis and osteoporosis. The use of a selective inhibitor of CatK was recently shown to delay OA progression in rabbits. However, the cellular mechanisms underlying these protective effects remain unexplored. We examined articular cartilage maintenance and joint bone remodeling using Ctsk null mice (Ctsk-/- ) which underwent destabilization of the medial meniscus (DMM). We found that Ctsk-/- mice displayed delayed remodeling of subchondral and calcified cartilage by osteoclasts and chodroclasts respectively in DMM-induced osteoarthritis. While WT mice displayed a more severe OA phenotype than Ctsk-/- mice at 16 weeks, higher subchondral bone volume and lower trabecular spacing were also observed in surgically-induced OA joints of Ctsk-/- mice. However, no differences were seen in non-surgical controls. During OA progression, TRAP+ osteoclast numbers were increased in both WT and Ctsk-/- mice. However, Ctsk-/- mice had fewer physis-derived chondroclasts than WT when OA was present. These data suggest that CatK may differentially regulate chondroclastogenesis in the growth plate. Targeted PCR arrays of RNA harvested from laser captured osteoclasts in the subchondral bone and chondroclasts in the growth plate demonstrated differential expression of Atp6v0d2, Tnfrsf11a, Ca2, Calcr, Ccr1, Gpr68, Itgb3, Nfatc1, and Syk genes between WT and Ctsk-/- mice at 8- and 16-weeks post-DMM. Our data provide insight into the cellular mechanisms by which cathepsin K deletion delays OA progression in mice.

Synergistic approach to localized delivery

Drug Delivery An improved remedy for osteoarthritis could involve localized delivery of an agent to the affected joints to reduce the disease progression, rather than the current use of systemic or local delivery of drugs that only treat the symptoms. Maudens et al. explored the potential for long-term delivery of kartogenin, a pathway activator that enhances articular cartilage protection, by combining two ideas for slow drug release. Using wet milling, they prepared nanocrystals of kartogenin, which dissolve over time, and then embedded them in biodegradable polymer microparticles. The drug-loaded particles were tested in vitro with human synoviocytes and in vivo in a mouse model, in which prolonged delivery and bioactivity of kartogenin were observed. Small 10.1002/smll.201703108 (2018).

Dried plum alleviates symptoms of inflammatory arthritis in TNF transgenic mice

Dried plum (DP), a rich source of polyphenols has been shown to have bone-preserving properties in both animal models of osteoporosis and postmenopausal women. We evaluated if DP alleviated the destruction of joints in transgenic mice (TG) that overexpress human tumor necrosis factor (TNF), a genetic model of rheumatoid arthritis (RA). A four-week treatment of 20% DP diet in TG slowed the onset of arthritis and reduced bone erosions in the joints compared to TG on a regular diet. This was associated with fewer tartrate-resistant acid phosphatase (TRAP) positive cells, suggesting decreased osteoclastogenesis. A DP diet also produced significant protection of articular cartilage and reduction of synovitis. Cultures of human synovial fibroblast in the presence of TNF showed a significant increase in inflammatory interleukin (IL)-1β, chemokines (monocyte chemoattractant protein-1: MCP1 & macrophage inflammatory protein-1 alpha: MIP1α), cartilage matrix metalloproteinases (MMP1&3), and an osteoclastogenic cytokine (receptor activator of nuclear factor-κB ligand: RANKL) compared to controls. Addition of neochlorogenic acid (NC), a major polyphenol in DP to these cultures resulted in down-regulation of these genes. In the cultures of mouse bone marrow macrophage, NC also repressed TNF-induced formation of osteoclasts and mRNA levels of cathepsin K and MMP9 through inhibition of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression and nuclear factor kappa B (NF-κB) activation. Our data suggested that dietary supplementation with DP inhibited TNF singling; leading to decreased erosions of bone and articular cartilage as well as synovitis.

Aliskiren has chondroprotective efficacy in a rat model of osteoarthritis through suppression of the local renin-angiotensin system.

The local renin-angiotensin system (RAS) has been reported to have an important role in the pathogenesis and progression of metabolic bone diseases, including osteoarthritis (OA). Aliskiren is the first in a new class of orally effective direct renin inhibitors and is approved for the treatment of hypertension in humans. However, its efficacy in patients with OA is unknown. A rat model of OA was induced to investigate the potential efficacy of aliskiren. Effects of aliskiren on the cartilage structure were detected by safranin O staining and its effects on the widths of the proliferation zone and hypertrophic zone (HZ) of chondrocytes were analyzed by Masson's staining. Tartate-resistant acid phosphatase staining was used to evaluate the effects of aliskiren on osteoclasts in the chondrocytes. Relative histological analyses were performed. Additionally, the expression levels of factors associated with osteoclast differentiation (receptor activator of nuclear factor κB ligand and osteoprotegerin), articular cartilage destruction [tumor necrosis factor-α (TNF-α) and matrix metalloproteinase 9] and osteoblast differentiation [runt related transcription factor 2 (Runx2)], along with RAS components (renin, renin-receptor, angiotensin type 1 receptor (AT1R), AT2R, angiotensin converting enzyme (ACE) and angiotensin II (Ang II)] were detected in samples from the proximal tibias. Aliskiren did not fully suppress the inflammatory reaction in OA model animals and had marginal regulatory effects on biochemical bone markers induced by OA. However, aliskiren attenuated cartilage destruction, abnormal cartilage cellularity and the expansion of the HZ of chondrocytes, and significantly attenuated the expression of interleukin-1, TNF-α, Runx2 and procollagen type I N-terminal propeptide. These chondroprotective properties were accompanied by reductions in the levels of RAS components (renin, Ang II, ACE and AT1R), indicating that aliskiren exerts multiple effects of on bone formation, osteoblast differentiation and articular cartilage protection via the RAS. OA activates the local bone RAS, inhibits bone formation and stimulates bone resorption. Aliskiren, a renin inhibitor, demonstrated chondroprotective efficacy in a rat model of OA through suppression of the local RAS.

Controlling joint instability delays the degeneration of articular cartilage in a rat model

Joint instability induced by anterior cruciate ligament (ACL) transection is commonly considered as a predisposing factor for osteoarthritis (OA) of the knee; however, the influence of re-stabilization on the protection of articular cartilage is unclear. The aim of this study was to evaluate the effect of joint re-stabilization on articular cartilage using an instability and re-stabilization ACL transection model. To induce different models of joint instability, our laboratory created a controlled abnormal joint movement (CAJM) group and an anterior cruciate ligament transection group (ACL-T). Seventy-five Wistar male rats were randomly assigned to the CAJM (n=30), ACL-T (n=30), or no treatment (INTACT) group (n=15). Cartilage changes were assessed with soft X-ray analysis, histological and immunohistochemistry analysis, and real-time polymerase chain reaction (PCR) analysis at 2, 4, and 12 weeks. Joint instability, as indicated by the difference in anterior displacement between the CAJM and ACL-T groups (P<0.001), and cartilage degeneration, as evaluated according to the Osteoarthritis Research Society International (OARSI) score, were significantly higher in the ACL-T group than the CAJM group at 12 weeks (P<0.001). Moreover, joint re-stabilization maintained cartilage structure (thickness [P<0.001], surface roughness [P<0.001], and glycosaminoglycan stainability [P<0.001]) and suppressed tumor necrosis factor-alpha (TNF-α) and caspase-3 at 4 weeks after surgery. Re-stabilization of joint instability may suppress inflammatory cytokines, thereby delaying the progression of OA. Joint instability is a substantial contributor to cartilage degeneration.

Chondroprotective effects of alpha-lipoic acid in a rat model of osteoarthritis

ABSTRACTObjective: The purpose of this study was to investigate whether alpha-lipoic acid (ALA) confers a chondroprotective effect on articular cartilage in rats with monosodium iodoacetate (MIA)-induced osteoarthritis (OA).Methods: Fifty male SD rats were divided into five groups, including SHAM-operated, MIA-induced OA, and three experimental groups treated with 50-, 100-, or 200-mg/kg ALA. After 14 d of ALA treatment, rats were sacrificed for joint macroscopic and histology assessments. The gene and protein expressions of markers related to chondrocyte phenotype, caspase proteins, NADPH oxidase 4 (Nox4), p22phox, activation of nuclear factor-κB (NF-κB), and endoplasmic reticulum (ER) stress were measured by Western blot analyses or qRT-PCR.Results: The results showed that MIA injection successfully induced OA by causing cartilage degeneration. Morphological and histological examinations demonstrated that ALA treatment, especially 200 mg/kg of ALA, significantly ameliorated cartilage degeneration in rats with MIA-induced OA. ALA could effectively increase the levels of the collagen type II and aggrecan genes and inhibit apoptosis-related proteins expression. ALA reduced biomakers of oxidative damage and over-expression levels of Nox4 and p22phox. ALA also suppressed ER stress and inhibited the activation of NF-κB pathway. Moreover, ALA obviously inhibited TNF-α secretion and Wnt/β-catenin signaling way.Conclusion: These findings indicated that ALA might be a potential therapeutic agent for the protection of articular cartilage against progression of OA through inhibition of oxidative stress, ER stress, inflammatory cytokine secretion, and Wnt/β-catenin activation.

Successful Total Meniscus Reconstruction Using a Novel Fiber-Reinforced Scaffold

Background: Meniscus injuries in the United States result in an estimated 850,000 surgical procedures each year. Although meniscectomies are the most commonly performed orthopaedic surgery, little advancement has been made in meniscus replacement and regeneration, and there is currently no total meniscus replacement device approved by the Food and Drug Administration. Hypothesis: A novel fiber-reinforced meniscus scaffold can be used as a functional total meniscus replacement. Study Design: Controlled laboratory study. Methods: A tyrosine-derived, polymer fiber–reinforced collagen sponge meniscus scaffold was evaluated mechanically (tensile and compressive testing) and histologically after 16 and 32 weeks of implantation in an ovine total meniscectomy model (N = 20; 16 implants plus 4 meniscectomies, divided equally over the 2 time periods). The extent of cartilage damage was also measured on tibial plateaus by use of toluidine blue surface staining and on femoral condyles by use of Mankin scores on histological slides. Results: Scaffolds induced formation of neomeniscus tissue that remained intact and functional, with breaking loads approximating 250 N at both 16 and 32 weeks compared with 552 N for native menisci. Tensile stiffness values (99 and 74 N/mm at 16 and 32 weeks, respectively) were also comparable with those of the native meniscus (147 N/mm). The compressive modulus of the neomeniscus tissue (0.33 MPa at both 16 and 32 weeks) was significantly increased compared with unimplanted (time 0) scaffolds (0.15 MPa). There was histological evidence of extensive tissue ingrowth and extracellular matrix deposition, with immunohistochemical evidence of types I and II collagen. Based on significantly decreased surface damage scores as well as Mankin scores, the scaffold implants provided greater protection of articular cartilage compared with the untreated total meniscectomy. Conclusion: This novel fiber-reinforced meniscus scaffold can act as a functional meniscus replacement, with mechanical properties similar to those of the native meniscus, while protecting the articular cartilage of the knee from the extensive damage after a total meniscectomy. Clinical Relevance: This meniscus replacement scaffold has the potential to improve surgical treatment and provide better long-term outcomes for those suffering from severe meniscus damage.

A new class of osteoarthritis therapeutic, extracellular matrix protection factor, alters cytokine production in chondrocytes (922.12)

Articular cartilage damage leads to osteoarthritis (OA), a disease characterized by altered cartilage homeostasis. Several cellular elements including growth factors and proteases are involved in this pathology. Our lab has developed a new class of therapeutic, extracellular matrix protection factors (ECPFs), that protect cartilage from the devastation associated with OA. ECPF‐1 targets the interaction between matrix metalloprotease 13 (MMP‐13) and transforming growth factor β (TGF‐β), but the cellular mechanism of ECPF‐1 chondroprotection is unknown. Inflammatory cytokines play a role in the pathology associated with OA, and are regulated, in some part, by TGF‐β biology. To test the downstream effects of blocking TGF‐β activation on cytokine production, cultured chondrocytes from embryonic avian sterna were treated for 24 hours with ECPF‐1 at 250nM, 2.5μM and 5.0μM concentrations and the production of the inflammatory cytokines, IL‐1β and TNF‐α, were monitored. Activated TGF‐β was reduced and production of IL‐1β and TNF‐α were decreased in response to ECPF‐1 treatment including an unexpected increase in these cytokines following 5.0μM addition of ECPF‐1. This biphasic effect of ECPF‐1 indicates a duality to the protective therapeutic nature and overall mechanism of action of ECPF‐1 in the protection of articular cartilage.