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The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 76881

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Dr. Masato Sato

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Department of Orthopedic Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
Interests: osteoarthritis; cartilage repair; regeneration; platelet rich plasma; MSCs
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Dear Colleagues,

Osteoarthritis of the knee (OAK) is the most common cause of disability in the worldwide population and is an intractable degenerative disease of the joint that is slow progressing and globally prevalent. It has heterogeneous phenotypes, including cartilage breakdown, synovitis, osteophyte formation, and bone marrow lesions. Histological studies show that OAK patients have variable degrees of synovitis, with higher levels of pro-inflammatory cytokines and infiltration of immune cells, predominantly macrophages. A fundamental treatment for OAK does not exist, and its development is an imperative. Currently, a conservative approach using intra-articular injections, such as so-called stem cell therapy and platelet rich plasma, has become widely available. Mesenchymal stem cells express a variety of growth factors and cytokines that aid in the repair of degraded tissue, restoration of normal tissue metabolism and, most importantly, counteracting inflammation. However, the mode of actions of these point-of-care treatments remains unclear. This Special Issue calls for original research papers, full reviews, and perspectives that address the progress and current knowledge of the molecular mechanisms of these point-of-care treatments for OAK.

Dr. Masato Sato
Guest Editor

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Keywords

osteoarthritis
molecular mechanisms
platelet rich plasma
MSCs
adipose cells
immune cells
cytokine
macrophage
inflammation
matrix degradation

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Published Papers (11 papers)

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10 pages, 4464 KiB

Open AccessArticle

E8002 Reduces Adhesion Formation and Improves Joint Mobility in a Rat Model of Knee Arthrofibrosis

by Seiya Takada, Kentaro Setoyama, Kosuke Norimatsu, Shotaro Otsuka, Kazuki Nakanishi, Akira Tani, Tomomi Nakakogawa, Ryoma Matsuzaki, Teruki Matsuoka, Harutoshi Sakakima, Salunya Tancharoen, Ikuro Maruyama, Eiichiro Tanaka, Kiyoshi Kikuchi and Hisaaki Uchikado

Int. J. Mol. Sci. 2022, 23(3), 1239; https://doi.org/10.3390/ijms23031239 - 22 Jan 2022

Cited by 3 | Viewed by 3143

Abstract

Knee arthrofibrosis is a common complication of knee surgery, caused by excessive scar tissue, which results in functional disability. However, no curative treatment has been established. E8002 is an anti-adhesion material that contains L-ascorbic acid, an antioxidant. We aimed to evaluate the efficacy of E8002 for the prevention of knee arthrofibrosis in a rat model, comprising injury to the surface of the femur and quadriceps muscle 1 cm proximal to the patella. Sixteen male, 8-week-old Sprague Dawley rats were studied: in the Adhesion group, haemorrhagic injury was induced to the quadriceps and bone, and in the E8002 group, an adhesion-preventing film was implanted between the quadriceps and femur after injury. Six weeks following injury, the restriction of knee flexion owing to fibrotic scarring had not worsened in the E8002 group but had worsened in the Adhesion group. The area of fibrotic scarring was smaller in the E8002 group than in the Adhesion group (p < 0.05). In addition, the numbers of fibroblasts (p < 0.05) and myofibroblasts (p < 0.01) in the fibrotic scar were lower in the E8002 group. Thus, E8002 reduces myofibroblast proliferation and fibrotic scar formation and improves the range of motion of the joint in a model of knee injury. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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15 pages, 5631 KiB

Open AccessArticle

Knee Osteoarthritis Progression Is Delayed in Silent Information Regulator 2 Ortholog 1 Knock-in Mice

by Tetsuya Yamamoto, Nobuaki Miyaji, Kiminari Kataoka, Kyohei Nishida, Kanto Nagai, Noriyuki Kanzaki, Yuichi Hoshino, Ryosuke Kuroda and Takehiko Matsushita

Int. J. Mol. Sci. 2021, 22(19), 10685; https://doi.org/10.3390/ijms221910685 - 1 Oct 2021

Cited by 6 | Viewed by 2303

Abstract

Overexpression of silent information regulator 2 ortholog 1 (SIRT1) is associated with beneficial roles in aging-related diseases; however, the effects of SIRT1 overexpression on osteoarthritis (OA) progression have not yet been studied. The aim of this study was to investigate OA progression in SIRT1-KI mice using a mouse OA model. OA was induced via destabilization of the medial meniscus using 12-week-old SIRT1-KI and wild type (control) mice. OA progression was evaluated histologically based on the Osteoarthritis Research Society International (OARSI) score at 4, 8, 12, and 16 weeks after surgery. The production of SIRT1, type II collagen, MMP-13, ADAMTS-5, cleaved caspase 3, Poly (ADP-ribose) polymerase (PARP) p85, acetylated NF-κB p65, interleukin 1 beta (IL-1β), and IL-6 was examined via immunostaining. The OARSI scores were significantly lower in SIRT1-KI mice than those in control mice at 8, 12, and 16 weeks after surgery. The proportion of SIRT1 and type II collagen-positive-chondrocytes was significantly higher in SIRT1-KI mice than that in control mice. Moreover, the proportion of MMP-13-, ADAMTS-5-, cleaved caspase 3-, PARP p85-, acetylated NF-κB p65-, IL-1β-, and IL-6-positive chondrocytes was significantly lower in SIRT1-KI mice than that in control mice. The mechanically induced OA progression was delayed in SIRT1-KI mice compared to that in control mice. Therefore, overexpression of SIRT1 may represent a mechanism for delaying OA progression. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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12 pages, 2322 KiB

Open AccessArticle

Development of Injectable Polydactyly-Derived Chondrocyte Sheets

by Shiho Wasai, Eriko Toyoda, Takumi Takahashi, Miki Maehara, Eri Okada, Ryoka Uchiyama, Tadashi Akamatsu, Masahiko Watanabe and Masato Sato

Int. J. Mol. Sci. 2021, 22(6), 3198; https://doi.org/10.3390/ijms22063198 - 21 Mar 2021

Cited by 4 | Viewed by 2691

Abstract

We are conducting a clinical study of the use of allogeneic polydactyly-derived chondrocyte sheets (PD sheets) for the repair of articular cartilage damage caused by osteoarthritis. However, the transplantation of PD sheets requires highly invasive surgery. To establish a less invasive treatment, we are currently developing injectable fragments of PD sheets (PD sheets-mini). Polydactyly-derived chondrocytes were seeded in RepCell™ or conventional temperature-responsive inserts and cultured. Cell counts and viability, histology, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qPCR), and flow cytometry were used to characterize PD sheets-mini and PD sheets collected from each culture. To examine the effects of injection on cell viability, PD sheets-mini were tested in four experimental conditions: non-injection control, 18 gauge (G) needle, 23G needle, and syringe only. PD sheets-mini produced similar amounts of humoral factors as PD sheets. No histological differences were observed between PD sheets and PD sheets-mini. Except for COL2A1, expression of cartilage-related genes did not differ between the two types of PD sheet. No significant differences were observed between injection conditions. PD sheets-mini have characteristics that resemble PD sheets. The cell viability of PD sheets-mini was not significantly affected by needle gauge size. Intra-articular injection may be a feasible, less invasive method to transplant PD sheets-mini. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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10 pages, 2746 KiB

Open AccessArticle

Local Administration of Low-Dose Nerve Growth Factor Antibody Reduced Pain in a Rat Osteoarthritis Model

by Yuan Tian, Tomohiro Onodera, Mohamad Alaa Terkawi, Koji Iwasaki, Ryosuke Hishimura, Dawei Liang, Takuji Miyazaki and Norimasa Iwasaki

Int. J. Mol. Sci. 2021, 22(5), 2552; https://doi.org/10.3390/ijms22052552 - 4 Mar 2021

Cited by 5 | Viewed by 3511

Abstract

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague–Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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16 pages, 3541 KiB

Open AccessArticle

Effect of Platelet-Rich Plasma on M1/M2 Macrophage Polarization

by Ryoka Uchiyama, Eriko Toyoda, Miki Maehara, Shiho Wasai, Haruka Omura, Masahiko Watanabe and Masato Sato

Int. J. Mol. Sci. 2021, 22(5), 2336; https://doi.org/10.3390/ijms22052336 - 26 Feb 2021

Cited by 59 | Viewed by 5079

Abstract

Osteoarthritis of the knee (OAK) is a chronic degenerative disease and progresses with an imbalance of cytokines and macrophages in the joint. Studies regarding the use of platelet-rich plasma (PRP) as a point-of-care treatment for OAK have reported on its effect on tissue repair and suppression of inflammation but few have reported on its effect on macrophages and macrophage polarization. Based on our clinical experience with two types of PRP kits Cellaid Serum Collection Set P type kit (leukocyte-poor-PRP) and an Autologous Protein Solution kit (APS leukocyte-rich-PRP), we investigated the concentrations of humoral factors in PRPs prepared from the two kits and the effect of humoral factors on macrophage phenotypes. We found that the concentrations of cell components and humoral factors differed between PRPs purified using the two kits; APS had a higher concentration of M1 and M2 macrophage related factors. The addition of PRP supernatants to the culture media of monocyte-derived macrophages and M1 polarized macrophages revealed that PRPs suppressed M1 macrophage polarization and promoted M2 macrophage polarization. This research is the first to report the effect of PRPs purified using commercial kits on macrophage polarization. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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17 pages, 930 KiB

Open AccessReview

Candidates for Intra-Articular Administration Therapeutics and Therapies of Osteoarthritis

by Eriko Toyoda, Miki Maehara, Masahiko Watanabe and Masato Sato

Int. J. Mol. Sci. 2021, 22(7), 3594; https://doi.org/10.3390/ijms22073594 - 30 Mar 2021

Cited by 17 | Viewed by 4597

Abstract

Osteoarthritis (OA) of the knee is a disease that significantly decreases the quality of life due to joint deformation and pain caused by degeneration of articular cartilage. Since the degeneration of cartilage is irreversible, intervention from an early stage and control throughout life is important for OA treatment. For the treatment of early OA, the development of a disease-modifying osteoarthritis drug (DMOAD) for intra-articular (IA) injection, which is attracting attention as a point-of-care therapy, is desired. In recent years, the molecular mechanisms involved in OA progression have been clarified while new types of drug development methods based on gene sequences have been established. In addition to conventional chemical compounds and protein therapeutics, the development of DMOAD from the new modalities such as gene therapy and oligonucleotide therapeutics is accelerating. In this review, we have summarized the current status and challenges of DMOAD for IA injection, especially for protein therapeutics, gene therapy, and oligonucleotide therapeutics. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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13 pages, 1180 KiB

Open AccessReview

Potential Mechanism of Action of Current Point-of-Care Autologous Therapy Treatments for Osteoarthritis of the Knee—A Narrative Review

by Jennifer Woodell-May, Kathleen Steckbeck and William King

Int. J. Mol. Sci. 2021, 22(5), 2726; https://doi.org/10.3390/ijms22052726 - 8 Mar 2021

Cited by 6 | Viewed by 3327

Abstract

Osteoarthritis (OA) is a progressive degenerative disease that manifests as pain and inflammation and often results in total joint replacement. There is significant interest in understanding how intra-articular injections made from autologous blood or bone marrow could alleviate symptoms and potentially intervene in the progression of the disease. There is in vitro an in vivo evidence that suggests that these therapies, including platelet-rich plasma (PRP), autologous anti-inflammatories (AAIs), and concentrated bone marrow aspirate (cBMA), can interrupt cartilage matrix degradation driven by pro-inflammatory cytokines. This review analyzes the evidence for and against inclusion of white blood cells, the potential role of platelets, and the less studied potential role of blood plasma when combining these components to create an autologous point-of-care therapy to treat OA. There has been significant focus on the differences between the various autologous therapies. However, evidence suggests that there may be more in common between groups and perhaps we should be thinking of these therapies on a spectrum of the same technology, each providing significant levels of anti-inflammatory cytokines that can be antagonists against the inflammatory cytokines driving OA symptoms and progression. While clinical data have demonstrated symptom alleviation, more studies will need to be conducted to determine whether these preclinical disease-modifying findings translate into clinical practice. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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24 pages, 1992 KiB

Open AccessReview

From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside

by Elena Rezuş, Alexandra Burlui, Anca Cardoneanu, Luana Andreea Macovei, Bogdan Ionel Tamba and Ciprian Rezuş

Int. J. Mol. Sci. 2021, 22(5), 2697; https://doi.org/10.3390/ijms22052697 - 7 Mar 2021

Cited by 46 | Viewed by 6875

Abstract

Osteoarthritis (OA) is currently the most widespread musculoskeletal condition and primarily affects weight-bearing joints such as the knees and hips. Importantly, knee OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathomechanisms. Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis. However, the pathogenic intricacies between the molecular pathways involved in OA prompted the study of certain drugs for more than one therapeutic target (amelioration of cartilage and bone changes, and synovial inflammation). Most clinical studies regarding knee OA focus mainly on improvement in pain and joint function and thus do not provide sufficient evidence on the possible disease-modifying properties of the tested drugs. Currently, there is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for these patients. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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16 pages, 1499 KiB

Open AccessReview

Potential of Exosomes for Diagnosis and Treatment of Joint Disease: Towards a Point-of-Care Therapy for Osteoarthritis of the Knee

by Miki Maehara, Eriko Toyoda, Takumi Takahashi, Masahiko Watanabe and Masato Sato

Int. J. Mol. Sci. 2021, 22(5), 2666; https://doi.org/10.3390/ijms22052666 - 6 Mar 2021

Cited by 17 | Viewed by 4888

Abstract

In the knee joint, articular cartilage injury can often lead to osteoarthritis of the knee (OAK). Currently, no point-of-care treatment can completely address OAK symptoms and regenerate articular cartilage to restore original functions. While various cell-based therapies are being developed to address OAK, exosomes containing various components derived from their cells of origin have attracted attention as a cell-free alternative. The potential for exosomes as a novel point-of-care treatment for OAK has been studied extensively, especially in the context of intra-articular treatments. Specific exosomal microRNAs have been identified as possibly effective in treating cartilage defects. Additionally, exosomes have been studied as biomarkers through their differences in body fluid composition between joint disease patients and healthy subjects. Exosomes themselves can be utilized as a drug delivery system through their manipulation and encapsulation of specific contents to be delivered to specific cells. Through the combination of exosomes with tissue engineering, novel sustained release drug delivery systems are being developed. On the other hand, many of the functions and activities of exosomes are unknown and challenges remain for clinical applications. In this review, the possibilities of intra-articular treatments utilizing exosomes and the challenges in using exosomes in therapy are discussed. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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15 pages, 13096 KiB

Open AccessReview

Recent Updates of Diagnosis, Pathophysiology, and Treatment on Osteoarthritis of the Knee

by Sunhee Jang, Kijun Lee and Ji Hyeon Ju

Int. J. Mol. Sci. 2021, 22(5), 2619; https://doi.org/10.3390/ijms22052619 - 5 Mar 2021

Cited by 238 | Viewed by 34307

Abstract

Osteoarthritis (OA) is a degenerative and chronic joint disease characterized by clinical symptoms and distortion of joint tissues. It primarily damages joint cartilage, causing pain, swelling, and stiffness around the joint. It is the major cause of disability and pain. The prevalence of OA is expected to increase gradually with the aging population and increasing prevalence of obesity. Many potential therapeutic advances have been made in recent years due to the improved understanding of the underlying mechanisms, diagnosis, and management of OA. Embryonic stem cells and induced pluripotent stem cells differentiate into chondrocytes or mesenchymal stem cells (MSCs) and can be used as a source of injectable treatments in the OA joint cavity. MSCs are known to be the most studied cell therapy products in cell-based OA therapy owing to their ability to differentiate into chondrocytes and their immunomodulatory properties. They have the potential to improve cartilage recovery and ultimately restore healthy joints. However, despite currently available therapies and advances in research, unfulfilled medical needs persist for OA treatment. In this review, we focused on the contents of non-cellular and cellular therapies for OA, and briefly summarized the results of clinical trials for cell-based OA therapy to lay a solid application basis for clinical research. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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12 pages, 5256 KiB

Open AccessCommentary

Characteristics of MSCs in Synovial Fluid and Mode of Action of Intra-Articular Injections of Synovial MSCs in Knee Osteoarthritis

by Ichiro Sekiya, Hisako Katano and Nobutake Ozeki

Int. J. Mol. Sci. 2021, 22(6), 2838; https://doi.org/10.3390/ijms22062838 - 11 Mar 2021

Cited by 21 | Viewed by 4565

Abstract

We have been studying mesenchymal stem cells (MSCs) in synovial fluid and the intra-articular injection of synovial MSCs in osteoarthritis (OA) knees. Here, mainly based on our own findings, we overview the characteristics of endogenous MSCs in the synovial fluid of OA knees and their mode of action when injected exogenously into OA knees. Many MSCs similar to synovial MSCs were detected in the synovial fluid of human OA knees, and their number correlated with the radiological OA grade. Our suspended synovium culture model demonstrated the release of MSCs from the synovium through a medium into a non-contacting culture dish. In OA knees, endogenous MSCs possibly mobilize in a similar manner from the synovium through the synovial fluid and act protectively. However, the number of mobilized MSCs is limited; therefore, OA progresses in its natural course. Synovial MSC injections inhibited the progression of cartilage degeneration in a rat OA model. Injected synovial MSCs migrated into the synovium, maintained their MSC properties, and increased the gene expressions of TSG-6, PRG-4, and BMP-2. Exogenous synovial MSCs can promote anti-inflammation, lubrication, and cartilage matrix synthesis in OA knees. Based on our findings, we have initiated a human clinical study of synovial MSC injections in OA knees. Full article

(This article belongs to the Special Issue The Mode of Actions of the Current Point-of-Care Treatments for Osteoarthritis of the Knee)

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