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Matrix Biology : Journal of the... Oct 2018Hyaline cartilages, fibrocartilages and elastic cartilages play multiple roles in the human body including bearing loads in articular joints and intervertebral discs,... (Review)
Review
Hyaline cartilages, fibrocartilages and elastic cartilages play multiple roles in the human body including bearing loads in articular joints and intervertebral discs, providing joint lubrication, forming the external ears and nose, supporting the trachea, and forming the long bones during development and growth. The structure and organization of cartilage's extracellular matrix (ECM) are the primary determinants of normal function. Most diseases involving cartilage lead to dramatic changes in the ECM which can govern disease progression (e.g., in osteoarthritis), cause the main symptoms of the disease (e.g., dwarfism caused by genetically inherited mutations) or occur as collateral damage in pathological processes occurring in other nearby tissues (e.g., osteochondritis dissecans and inflammatory arthropathies). Challenges associated with cartilage diseases include poor understanding of the etiology and pathogenesis, delayed diagnoses due to the aneural nature of the tissue and drug delivery challenges due to the avascular nature of adult cartilages. This narrative review provides an overview of the clinical and pathological features as well as current treatment options available for various cartilage diseases. Late breaking advances are also described in the quest for development and delivery of effective disease modifying drugs for cartilage diseases including osteoarthritis, the most common form of arthritis that affects hundreds of millions of people worldwide.
Topics: Cartilage Diseases; Cartilage, Articular; Disease Progression; Extracellular Matrix; Humans; Mutation
PubMed: 29803938
DOI: 10.1016/j.matbio.2018.05.005 -
International Journal of Molecular... Dec 2022Knee osteoarthritis presents higher incidences than other joints, with increased prevalence during aging. It is a progressive process and may eventually lead to... (Review)
Review
Knee osteoarthritis presents higher incidences than other joints, with increased prevalence during aging. It is a progressive process and may eventually lead to disability. Mesenchymal stem cells (MSCs) are expected to repair damaged issues due to trilineage potential, trophic effects, and immunomodulatory properties of MSCs. Intra-articular MSC injection was reported to treat knee osteoarthritis in many studies. This review focuses on several issues of intra-articular MSC injection for knee osteoarthritis, including doses of MSCs applied for injection and the possibility of cartilage regeneration following MSC injection. Intra-articular MSC injection induced hyaline-like cartilage regeneration, which could be seen by arthroscopy in several studies. Additionally, anatomical, biomechanical, and biochemical changes during aging and other causes participate in the development of knee osteoarthritis. Conversely, appropriate intervention based on these anatomical, biomechanical, biochemical, and functional properties and their interactions may postpone the progress of knee OA and facilitate cartilage repair induced by MSC injection. Hence, post-injection rehabilitation programs and related mechanisms are discussed.
Topics: Humans; Osteoarthritis, Knee; Treatment Outcome; Cartilage, Articular; Knee Joint; Injections, Intra-Articular; Mesenchymal Stem Cells; Mesenchymal Stem Cell Transplantation
PubMed: 36613502
DOI: 10.3390/ijms24010059 -
Acta Biomaterialia Mar 2022The ability of articular cartilage to repair itself is limited because it lacks blood vessels, nerves, and lymph tissue. Once damaged, it can lead to joint swelling and... (Review)
Review
The ability of articular cartilage to repair itself is limited because it lacks blood vessels, nerves, and lymph tissue. Once damaged, it can lead to joint swelling and pain, accelerating the progression of osteoarthritis. To date, complete regeneration of hyaline cartilage exhibiting mechanical properties remains an elusive goal, despite the many available technologies. The inflammatory milieu created by cartilage damage is critical for chondrocyte death and hypertrophy, extracellular matrix breakdown, ectopic bone formation, and progression of cartilage injury to osteoarthritis. In the inflammatory microenvironment, mesenchymal stem cells (MSCs) undergo aberrant differentiation, and chondrocytes begin to convert or dedifferentiate into cells with a fibroblast phenotype, thereby resulting in fibrocartilage with poor mechanical qualities. All these factors suggest that inflammatory problems may be a major stumbling block to cartilage repair. To produce a milieu conducive to cartilage repair, multi-dimensional management of the joint inflammatory microenvironment in place and time is required. Therefore, this calls for elucidation of the immune microenvironment of cartilage repair after injury. This review provides a brief overview of: (1) the pathogenesis of cartilage injury; (2) immune cells in cartilage injury and repair; (3) effects of inflammatory cytokines on cartilage repair; (4) clinical strategies for treating cartilage defects; and (5) strategies for targeted immunoregulation in cartilage repair. STATEMENT OF SIGNIFICANCE: Immune response is increasingly considered the key factor affecting cartilage repair. It has both negative and positive regulatory effects on the process of regeneration and repair. Proinflammatory factors are secreted in large numbers, and necrotic cartilage is removed. During the repair period, immune cells can secrete anti-inflammatory factors and chondrogenic cytokines, which can inhibit inflammation and promote cartilage repair. However, inflammatory factors persist, which accelerate the degradation of the cartilage matrix. Furthermore, in an inflammatory microenvironment, MSCs undergo abnormal differentiation, and chondrocytes begin to transform or dedifferentiate into fibroblast-like cells, forming fibrocartilage with poor mechanical properties. Consequently, cartilage regeneration requires multi-dimensional regulation of the joint inflammatory microenvironment in space and time to make it conducive to cartilage regeneration.
Topics: Cartilage Diseases; Cartilage, Articular; Cell Differentiation; Chondrocytes; Chondrogenesis; Humans; Osteoarthritis; Tissue Engineering
PubMed: 34896634
DOI: 10.1016/j.actbio.2021.12.006 -
Advanced Drug Delivery Reviews Jun 2019Once damaged, articular cartilage has a limited potential to repair. Clinically, a repair tissue is formed, yet, it is often mechanically inferior fibrocartilage. The... (Review)
Review
Once damaged, articular cartilage has a limited potential to repair. Clinically, a repair tissue is formed, yet, it is often mechanically inferior fibrocartilage. The use of monolayer expanded versus naïve cells may explain one of the biggest discrepancies in mesenchymal stromal/stem cell (MSC) based cartilage regeneration. Namely, studies utilizing monolayer expanded MSCs, as indicated by numerous in vitro studies, report as a main limitation the induction of type X collagen and hypertrophy, a phenotype associated with endochondral bone formation. However, marrow stimulation and transfer studies report a mechanically inferior collagen I/II fibrocartilage as the main outcome. Therefore, this review will highlight the collagen species produced during the different therapeutic approaches. New developments in scaffold design and delivery of therapeutic molecules will be described. Potential future directions towards clinical translation will be discussed. New delivery mechanisms are being developed and they offer new hope in targeted therapeutic delivery.
Topics: Animals; Fibrocartilage; Humans; Hyaline Cartilage
PubMed: 30605736
DOI: 10.1016/j.addr.2018.12.015 -
Nature Communications May 2022Damaged hyaline cartilage has no capacity for self-healing, making osteoarthritis (OA) "difficult-to-treat". Cartilage destruction is central to OA patho-etiology and is...
Damaged hyaline cartilage has no capacity for self-healing, making osteoarthritis (OA) "difficult-to-treat". Cartilage destruction is central to OA patho-etiology and is mediated by matrix degrading enzymes. Here we report decreased expression of miR-17 in osteoarthritic chondrocytes and its deficiency contributes to OA progression. Supplementation of exogenous miR-17 or its endogenous induction by growth differentiation factor 5, effectively prevented OA by simultaneously targeting pathological catabolic factors including matrix metallopeptidase-3/13 (MMP3/13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2). Single-cell RNA sequencing of hyaline cartilage revealed two distinct superficial chondrocyte populations (C1/C2). C1 expressed physiological catabolic factors including MMP2, and C2 carries synovial features, together with C3 in the middle zone. MiR-17 is highly expressed in both superficial and middle chondrocytes under physiological conditions, and maintains the physiological catabolic and anabolic balance potentially by restricting HIF-1α signaling. Together, this study identified dual functions of miR-17 in maintaining cartilage homeostasis and prevention of OA.
Topics: Cartilage, Articular; Cells, Cultured; Chondrocytes; Homeostasis; Humans; Matrix Metalloproteinase 13; MicroRNAs; Osteoarthritis
PubMed: 35508470
DOI: 10.1038/s41467-022-30119-8 -
Sports Health 2016Isolated chondral and osteochondral defects of the knee are a difficult clinical challenge, particularly in younger patients for whom alternatives such as partial or... (Review)
Review
CONTEXT
Isolated chondral and osteochondral defects of the knee are a difficult clinical challenge, particularly in younger patients for whom alternatives such as partial or total knee arthroplasty are rarely advised. Numerous surgical techniques have been developed to address focal cartilage defects. Cartilage treatment strategies are characterized as palliation (eg, chondroplasty and debridement), repair (eg, drilling and microfracture [MF]), or restoration (eg, autologous chondrocyte implantation [ACI], osteochondral autograft [OAT], and osteochondral allograft [OCA]).
EVIDENCE ACQUISITION
PubMed was searched for treatment articles using the keywords knee, articular cartilage, and osteochondral defect, with a focus on articles published in the past 5 years.
STUDY DESIGN
Clinical review.
LEVEL OF EVIDENCE
Level 4.
RESULTS
In general, smaller lesions (<2 cm(2)) are best treated with MF or OAT. Furthermore, OAT shows trends toward greater longevity and durability as well as improved outcomes in high-demand patients. Intermediate-size lesions (2-4 cm(2)) have shown fairly equivalent treatment results using either OAT or ACI options. For larger lesions (>4 cm(2)), ACI or OCA have shown the best results, with OCA being an option for large osteochondritis dissecans lesions and posttraumatic defects.
CONCLUSION
These techniques may improve patient outcomes, though no single technique can reproduce normal hyaline cartilage.
Topics: Arthroplasty; Cartilage; Cartilage, Articular; Chondrocytes; Debridement; Genetic Therapy; Guided Tissue Regeneration; Humans; Knee Injuries; Stem Cell Transplantation; Transplantation, Autologous; Transplantation, Homologous
PubMed: 26502188
DOI: 10.1177/1941738115611350 -
Osteoarthritis and Cartilage Oct 2022We conducted a systematic review in order to understand the relationship between imaging-visualised meniscus pathologies, hyaline cartilage, joint replacement and pain... (Review)
Review
OBJECTIVE
We conducted a systematic review in order to understand the relationship between imaging-visualised meniscus pathologies, hyaline cartilage, joint replacement and pain in knee osteoarthritis (OA).
DESIGN
A search of the Medline, Excerpta Medica database (EMBASE) and Cochrane library databases was performed for original publications reporting association between imaging-detected meniscal pathology (extrusion or tear/damage) and longitudinal and cross-sectional assessments of hyaline articular cartilage loss [assessed on magnetic resonance imaging (MRI)], incident joint replacement and pain (longitudinal and cross-sectional) in knee OA. Each association was qualitatively characterised by a synthesis of data from each analysis, based upon study design and quality scoring (including risk of bias assessment and adequacy of covariate adjustment using Cochrane recommended methodology).
RESULTS
In total 4,878 abstracts were screened and 82 publications were included (comprising 72 longitudinal analyses and 49 cross-sectional). Using high quality, well-adjusted data, meniscal extrusion and meniscal tear/damage were associated with longitudinal progression of cartilage loss, cross-sectional cartilage loss severity and joint replacement, independently of age, sex and body mass index (BMI). Medial and lateral meniscal tears were associated with cartilage loss when they occurred in the body and posterior horns, but not the anterior horns. There was a lack of high quality, well-adjusted meniscal pathology and pain publications and no clear independent association between meniscal extrusion or tear/damage with pain severity, progression in pain or incident frequent knee symptoms.
CONCLUSION
Meniscal features have strong associations with cartilage loss and joint replacement in knee OA, but weak associations with knee pain. Systematic review PROSPERO registration number: CRD 42020210910.
Topics: Arthroplasty, Replacement; Cartilage, Articular; Cross-Sectional Studies; Humans; Knee Joint; Magnetic Resonance Imaging; Menisci, Tibial; Osteoarthritis, Knee; Pain
PubMed: 35963512
DOI: 10.1016/j.joca.2022.08.002 -
Nature Communications Jun 2014The ability to print and pattern all the components that make up a tissue (cells and matrix materials) in three dimensions to generate structures similar to tissues is...
The ability to print and pattern all the components that make up a tissue (cells and matrix materials) in three dimensions to generate structures similar to tissues is an exciting prospect of bioprinting. However, the majority of the matrix materials used so far for bioprinting cannot represent the complexity of natural extracellular matrix (ECM) and thus are unable to reconstitute the intrinsic cellular morphologies and functions. Here, we develop a method for the bioprinting of cell-laden constructs with novel decellularized extracellular matrix (dECM) bioink capable of providing an optimized microenvironment conducive to the growth of three-dimensional structured tissue. We show the versatility and flexibility of the developed bioprinting process using tissue-specific dECM bioinks, including adipose, cartilage and heart tissues, capable of providing crucial cues for cells engraftment, survival and long-term function. We achieve high cell viability and functionality of the printed dECM structures using our bioprinting method.
Topics: Adipose Tissue; Animals; Bioprinting; Cartilage; Extracellular Matrix; Heart; Humans; Hyaline Cartilage; Ink; Mesenchymal Stem Cells; Printing, Three-Dimensional; Stem Cells; Swine; Tissue Engineering; Tissue Scaffolds
PubMed: 24887553
DOI: 10.1038/ncomms4935 -
Nature Medicine Dec 2022Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3... (Randomized Controlled Trial)
Randomized Controlled Trial
Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin αβ on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial ( NCT02491281 ; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial ( NCT04864392 ) in patients with knee OA.
Topics: Humans; Osteoarthritis, Knee; Chondrocytes; Cartilage, Articular; Signal Transduction; Angiopoietins; Angiopoietin-Like Protein 3
PubMed: 36456835
DOI: 10.1038/s41591-022-02059-9 -
Development (Cambridge, England) Jan 2022Amputation injuries in mammals are typically non-regenerative; however, joint regeneration is stimulated by BMP9 treatment, indicating the presence of latent articular...
Amputation injuries in mammals are typically non-regenerative; however, joint regeneration is stimulated by BMP9 treatment, indicating the presence of latent articular chondrocyte progenitor cells. BMP9 induces a battery of chondrogenic genes in vivo, and a similar response is observed in cultures of amputation wound cells. Extended cultures of BMP9-treated cells results in differentiation of hyaline cartilage, and single cell RNAseq analysis identified wound fibroblasts as BMP9 responsive. This culture model was used to identify a BMP9-responsive adult fibroblast cell line and a culture strategy was developed to engineer hyaline cartilage for engraftment into an acutely damaged joint. Transplanted hyaline cartilage survived engraftment and maintained a hyaline cartilage phenotype, but did not form mature articular cartilage. In addition, individual hypertrophic chondrocytes were identified in some samples, indicating that the acute joint injury site can promote osteogenic progression of engrafted hyaline cartilage. The findings identify fibroblasts as a cell source for engineering articular cartilage and establish a novel experimental strategy that bridges the gap between regeneration biology and regenerative medicine.
Topics: Animals; Cell Differentiation; Cells, Cultured; Chondrocytes; Chondrogenesis; Fibroblasts; Growth Differentiation Factor 2; Hyaline Cartilage; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Regeneration; Tissue Engineering
PubMed: 35005773
DOI: 10.1242/dev.200249