The 100 Most Cited Articles on the Applications of Stem Cells in Osteoarthritis: A Bibliometric Analysis

Abstract

Background: Stem cells have been applied in the treatment of OA, which had attracted wide attention. However, the research area is relatively extensive, and the research level is variable. In this study, we reviewed the mechanisms and clinical applications of stem cells in OA by using bibliometric analysis for the first time. We also revealed the characteristics, superior results and developmental trends in this field.

Methods: The Web of Science core collection database was used to search articles related to the application of stem cells in OA. We collected the general information from the top 100 cited articles. We analyzed and evaluated the articles according to publication number, journals, institutions, countries, keywords and extended keywords.

Results: The 100 most cited articles were cited from 129 to 1353 times mainly reviews and original articles. These articles were published from 2001 to 2017 and distributed evenly in America, East Asia and European countries. The United States contributed most in published number and international cooperation. The top ten institutions are mainly major universities and Duke University published a maximum of 10 articles. In terms of journals ,57 articles were published in the top ten journals. The keywords were divided into 8 categories from molecular mechanisms to clinical application.

Conclusions: In our study, we found that mesenchymal stem cells (MSCs) which could repair articular cartilage and inhibit local inflammation, are the most widely applied in research and treatment of OA. TGF-βwas crucial during the process. Exosomes are regarded as the active ingredients in stem cell therapy for OA. Microtissue engineering will contribute to accurate and effective stem cell therapy. The findings of our study will contribute to the continuous development of research and direct the research of stem cells in OA.

Introduction

Osteoarthritis (OA) is a common joint disease associated with the aging of the population, an increasing number of obese people, and participation in sports, which reduces the quality of life of patients¹. According to statistics, OA is the fourth most common cause of reduced physical function in the world. It is characterized by the destruction of articular cartilage and abnormal proliferation of osteophytes, and it produces pathological variation, joint pain, limited mobility and joint deformities as clinical manifestations. At present, traditional methods of intervention for osteoarthritis, such as functional exercises, physical therapy, lifestyle changes and the use of analgesics, which are the first choices for treatment, can only temporarily relieve symptoms but cannot improve the pathogenesis of osteoarthritis or reverse the process of osteoarthritis². For more serious cases, joint replacement surgery is required; this method can be useful, but it is not suitable for young patients with a large amount of activity³. A consensus can be reached that joint degeneration and local inflammation are regarded as important factors leading to OA based on current studies^4,5. The key to successful treatment of osteoarthritis is cartilage regeneration and the control of local inflammation. The research of treatment methods will focus on these two aspects.

Stem cells, which are a kind of seed cell with multiple differentiation potentials, have shown their advantages in the treatment of osteoarthritic cartilage lesions in recent years. In addition to their differentiation potential, stem cells can also secrete a variety of enzymes and nutritional factors to participate in the paracrine process, including growth factors, cytokines, and chemokines that play a role in anti-apoptosis, anti-fibrosis, antioxidation, anti-inflammatory, and angiogenesis promotion. In particular, autologous mesenchymal stem cells (MSCs) isolated from bone marrow, adipose tissue and umbilical cord have the potential to differentiate into cartilage. However, there are many types of stem cells, and the efficacy of different types remains to be compared. In addition, modifying stem cells based on the type and degree of OA can greatly improve the effect of treatment.

Bibliometric analysis is a cross-disciplinary approach using mathematical and statistical methods to analyze the quantity and quality of publications⁶. In view of the effect of stem cell therapy in clinical prevention and treatment of OA, this study aimed to discuss the role of stem cells in osteoarthritis and attempt to direct the research for the first time according to the bibliometric analysis of the 100 most cited articles. The results can be used to evaluate the research status and predict the developmental trend of the application of stem cells in OA.

Materials And Methods

Results

The 100 most cited articles were collected according to the number of times cited number in the WoS core and sorted in descending order and included 65 articles (one of the articles was also a proceedings paper) and 35 reviews (Table 1). The number of citations ranged from a maximum of 1353 times to a minimum of 129. We collated the general information for these articles including the publication year, authors, journal, institutions and countries and examined the article characteristics by using bibliometric analysis.

Discussion

With the development of regenerative medicine technology, stem cell therapy regenerative medicine technology has been used in the field of cartilage defects and the promotion of cartilage regeneration. Due to the wide range of research and differences at the article level, it was difficult to perform a comprehensive comparison and integration. There are different types of stem cells and the mechanisms are still unclear. Thus, we decided to select the 100 most cited articles on stem cell applications in OA in terms of the number of citations in the WoS core. We aimed to review the research of stem cells in osteoarthritis, analyze research hotspots and predicte developmental trends.

After content analysis and hotspot summary of these articles, we selected 215 keywords and classified them into 8 clusters, each of which had a theme related to the study of stem cell applications in osteoarthritis. These clusters specifically explored stem cell treatment of osteoarthritis from investigation of the molecular mechanism to clinical evaluation. We found that MSCs were the most widely applied cells and the research focused on the process of cartilage repair and exosome secretion. Mesenchymal stem cells are the direct precursor cells of chondrocytes¹². Researchers have tried to use various methods to induce MSCs to differentiate into cartilage and obtained effective results in animal experiments¹³. On the other hand, modulation of transforming growth factor β (TGF-β) plays an important role in stem cell therapy of OA. Increasing the production of TGF-β in subchondral bone could cause physiological changes in cartilage and lead to the progression of osteoarthritis¹⁴. MSCs regulated local TGF-β level at the optimal concentrations, and TGF-β promoted chondrocyte differentiation of MSCs in return^15,16. Other studies regarded exosomes which are small membrane vesicles containing complexes of RNA and proteins that participate in the intercellular communication, as the active components in treatment¹⁷. In animal experiments, exosomes extracted from MSCs were injected into the articular tissue of rats, which inhibited the inflammatory response and repaired injured cartilage^18,19. Small RNAs in exosomes decrease the expression of inflammatory factors and improve oxidative stress states^20,21. The next steps are the targeting of exosomes and the identification of small RNAs that specifically regulate the expression of TGF-β, which would improve the effectiveness of treatment.

Judging from the content of these 100 articles, the progress in research on stem cell applications in osteoarthritis has been relatively rapid and comprehensive. However, simple local injection of stem cells has great limitations, such as the huge number of cells required, long treatment cycle, extremely high costs and perhaps side effects. In addition, the environment used for stem cell culture in vitro is very different from the real stem cell microenvironment. It is difficult for stem cells cultured in vitro to emulate the morphology and function of cells in vivo or to maintain the relevant characteristics in vivo for a long time. However, scientists have investigated the microenvironment of stem cells in bone marrow at single cell level²². Tissue engineering technology could reproduce the microenvironment on which stem cells depend and improve the efficacy of therapy²³. "Microtissue engineering" is a research field that has emerged to address abovementioned challenges, aiming to construct a precise and controllable cell "microenvironment" with bionic structures and functions on a "microscale"^24,25. In clinical applications, stem cells were coated with internal implants by tissue engineering methods to ensure their function and, the follow-up results indicated that this approach was effective. The goal of the current research is to modify the dosage of stem cells to achieve individualized and precise treatment assisted with microtissue engineering, which would greatly enhance the effectiveness.

Stem cell therapy has been an effective measure for many diseases including the recent outbreak of COVID-19²⁶. The characteristics of stem cells can be attributed to the potential for multidirectional differentiation and the ability to internally regulate process by the secretion of exosomes, which ensures that they can repair damaged tissues and maintain homeostasis. A variety of mesenchymal stem cells have been used in the treatment of osteoarthritis and analyzed for their efficacy. After comparison, bone marrow MSCs had the optimal therapeutic effect but they have few sources and are difficult to sample, whereas synovial MSCs had the strongest ability to repair cartilage but were limited in inflammation control; adipose tissue MSCs were regarded as excellent cell sources but with potent trend toward adipogenesis, and umbilical MSCs had been proven to have the capacity for OA treatment and the repair of cartilage in 3D culture with greater potency for clinical transformation²⁷. Thus, the targeted design of umbilical cord stem cells will result in a breakthrough in the future.

Finally, there are some limitations in our study. Because the total number of articles in this field is still relatively small, the 100 most cited articles are not very representative. The inclusion criterion of “English” and the use of a single database (WoS core) would cause us to miss some articles. The shortcoming of this analysis method is that articles are sorted in terms of the citation counts, which are relevant to the published years. In short, our study can still determine the research hotspots and predict the development trends to the greatest extent although limitations exist.

Conclusion

In our study, we found that MSCs, which transform into chondrocytes under specific induction conditions in vivo and in vitro to repair articular cartilage, are most widely used in basic science and are the best choice in clinical applications. MSCs were induced to differentiate into chondrocytes by secretion of a variety of factors, of which TGFβwas crucial during the process; at the same time, TGFβ inhibited the progression of local inflammation, which promoted the self-repair ability of local damaged tissues and achieved the purpose of intervention. Exosomes are regarded as the active components of stem cells for the treatment of OA. Microtissue engineering will contribute to accurate and effective stem cell therapy. The findings of our study will contribute to the continuous development and direction of the research of stem cells in OA.

Abbreviations

Declarations

Availability of Data and Materials

All data are included in the text and supplementary information.

Ethics Approval and Consent to Participate

Not applicable

Consent for publication

Not applicable

Funding

None. There was no funding received for this research.

Acknowledgement

The authors thank Dr Yue Zhu for his help

Author contributions

Keda Yang and Siming Zhou contributed equally to this work

Conceptualization, LT; Data curation, SZ; Formal analysis, KY; Funding acquisition, KY; Investigation, SZ; Methodology, SZ; Project administration, LT; Resources, KY; Software, SZ; Validation, SZ; Writing – original draft, KY; Writing – review & editing, LT.

All authors read and approved the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

1 Hunter, D. J. & Bierma-Zeinstra, S. Osteoarthritis. Lancet (London, England)393, 1745-1759, doi:10.1016/s0140-6736(19)30417-9 (2019).

2 Wang, S. Y. et al. Physical therapy interventions for knee pain secondary to osteoarthritis: a systematic review. Annals of internal medicine157, 632-644, doi:10.7326/0003-4819-157-9-201211060-00007 (2012).

3 Glyn-Jones, S. et al. Osteoarthritis. Lancet (London, England)386, 376-387, doi:10.1016/s0140-6736(14)60802-3 (2015).

4 Deng, Y. et al. Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation. Nature communications9, 4564, doi:10.1038/s41467-018-07022-2 (2018).

5 Wan, W. L. et al. An In Situ Depot for Continuous Evolution of Gaseous H(2) Mediated by a Magnesium Passivation/Activation Cycle for Treating Osteoarthritis. 57, 9875-9879, doi:10.1002/anie.201806159 (2018).

6 Noyons, E. C. M., Moed, H. F. & Luwel, M. Combining mapping and citation analysis for evaluative bibliometric purposes: A bibliometric study. Journal of the Association for Information Ence & Technology50, - (2010).

7 Zhang, T. et al. Research trends on the relationship between Microbiota and Gastric Cancer: A Bibliometric Analysis from 2000 to 2019. Journal of Cancer11, 4823-4831, doi:10.7150/jca.44126 (2020).

8 Li, S. et al. Bibliometric Analysis of Pediatric Liver Transplantation Research in PubMed from 2014 to 2018. Medical science monitor : international medical journal of experimental and clinical research26, e922517, doi:10.12659/msm.922517 (2020).

9 Athanasou, N. A., Quinn, J. & McGee, J. O. Leucocyte common antigen is present on osteoclasts. The Journal of pathology153, 121-126, doi:10.1002/path.1711530205 (1987).

10 McGinnes, K. et al. Growth and detection of human bone marrow B-lineage colonies. Blood76, 896-905 (1990).

11 Marini, J. C. & Forlino, A. Replenishing cartilage from endogenous stem cells. The New England journal of medicine366, 2522-2524, doi:10.1056/NEJMcibr1204283 (2012).

12 Nombela-Arrieta, C., Ritz, J. & Silberstein, L. E. The elusive nature and function of mesenchymal stem cells. Nature reviews. Molecular cell biology12, 126-131, doi:10.1038/nrm3049 (2011).

13 Johnson, K. et al. A stem cell-based approach to cartilage repair. Science (New York, N.Y.)336, 717-721, doi:10.1126/science.1215157 (2012).

14 Bush, J. R. & Beier, F. TGF-β and osteoarthritis--the good and the bad. Nature medicine19, 667-669, doi:10.1038/nm.3228 (2013).

15 Ma, N., Teng, X., Zheng, Q. & Chen, P. The regulatory mechanism of p38/MAPK in the chondrogenic differentiation from bone marrow mesenchymal stem cells. Journal of orthopaedic surgery and research14, 434, doi:10.1186/s13018-019-1505-2 (2019).

16 Park, M. J. et al. Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis. 203, 127-136, doi:10.4049/jimmunol.1800006 (2019).

17 Kalluri, R. & LeBleu, V. S. The biology, function, and biomedical applications of exosomes. 367, doi:10.1126/science.aau6977 (2020).

18 Zhang, S. et al. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis and cartilage24, 2135-2140, doi:10.1016/j.joca.2016.06.022 (2016).

19 He, L. et al. Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis. Stem cell research & therapy11, 276, doi:10.1186/s13287-020-01781-w (2020).

20 Jin, Z., Ren, J. & Qi, S. Exosomal miR-9-5p secreted by bone marrow-derived mesenchymal stem cells alleviates osteoarthritis by inhibiting syndecan-1. Cell and tissue research381, 99-114, doi:10.1007/s00441-020-03193-x (2020).

21 Meng, Q. & Qiu, B. Exosomal MicroRNA-320a Derived From Mesenchymal Stem Cells Regulates Rheumatoid Arthritis Fibroblast-Like Synoviocyte Activation by Suppressing CXCL9 Expression. Frontiers in physiology11, 441, doi:10.3389/fphys.2020.00441 (2020).

22 Tikhonova, A. N. et al. The bone marrow microenvironment at single-cell resolution. Nature569, 222-228, doi:10.1038/s41586-019-1104-8 (2019).

23 West-Livingston, L. N., Park, J. & Lee, S. J. The Role of the Microenvironment in Controlling the Fate of Bioprinted Stem Cells. doi:10.1021/acs.chemrev.0c00126 (2020).

24 Flood, P., Alvarez, L. & Reynaud, E. G. Free-floating epithelial micro-tissue arrays: a low cost and versatile technique. Biofabrication8, 045006, doi:10.1088/1758-5090/8/4/045006 (2016).

25 Ahmad, T. et al. Fabrication of in vitro 3D mineralized tissue by fusion of composite spheroids incorporating biomineral-coated nanofibers and human adipose-derived stem cells. Acta biomaterialia74, 464-477, doi:10.1016/j.actbio.2018.05.035 (2018).

26 Lammers, T. & Sofias, A. M. Dexamethasone nanomedicines for COVID-19. 15, 622-624, doi:10.1038/s41565-020-0752-z (2020).

27 Ni, Z. et al. Exosomes: roles and therapeutic potential in osteoarthritis. Bone research8, 25, doi:10.1038/s41413-020-0100-9 (2020).