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Review article


May intra-articular injections of autologous mesenchymal stem cells (MSCs) promote cartilage regeneration in human knee osteoarthritis?


E. Carlos RODRIGUEZ-MERCHAN, MD, PhD 


Department of Orthopaedic Surgery, La Paz University Hospital, Madrid, Spain; and School of Medicine, Autonomous University, Madrid, Spain.




Running title: Intra-articular injections of MSCs in knee OA






Correspondence: E. C. Rodr�guez-Merch�n, Department of Orthopaedic Surgery, La Paz University Hospital, Paseo de la Castellana 261, 28046-Madrid, Spain. E-mail:  HYPERLINK "mailto:ecrmerchan@gmx.es" ecrmerchan@gmx.es


ABSTRACT
BACKGROUND: Knee osteoarthritis (OA) represents an enormous societal burden. Yet no approved procedure prevents the progressive destruction of the osteoarthritic joint. QUESTION: This review aims to define the role of intra-articular injections of autologous mesenchymal stem cells (MSCs) in promoting cartilage regeneration in knee OA. METHODS: A PubMed (MEDLINE) and Cochrane Library search related to MSCs and knee OA were analyzed. Articles were searched using the following key words: stem cells and knee OA. A total of 123 reports were found but only 16 very selected and reviewed. The main criterion for selection was that the articles were focused in the aforementioned question. RESULTS: Local delivery (intra-articular injection) of autologous MSCs has produced promising outcomes in 13 experimental models of knee OA. However, only 3 low-quality clinical studies have been reported so far on the role of MSCs injections in knee OA. Study design weakness prevented effective comparison of the efficacy of MSC injections with that of other treatments for relief of pain and other outcomes in human knee OA. The consistency of evidence of the clinical studies was low because of many uncontrolled variables. CONCLUSIONS: Animal experiments suggest that intra-articular injections of autologous MSCs can have the potential to promote cartilage regeneration in knee OA. Taking into account the low quality of the data reported in clinical studies, my conclusion is that intra-articular injections of autologous MSCs in knee OA is a treatment that is still experimental.
Key words: knee, osteoarthritis, intra-articular, injections, autologous, mesenchymal stem cells
INTRODUCTION
Knee osteoarthritis (OA), a prevalent chronic disease with a striking impact on quality of life, represents an enormous societal burden. Yet no procedure prevents the progressive destruction of the OA joint [1]. According to Barry et al [2] mesenchymal stem cells (MSCs) have the capacity to differentiate into a variety of connective tissue cells including cartilage. These multipotent cells have been isolated from bone marrow and from other adult tissues including skeletal muscle, fat and synovium. Because of their multipotentiality and capacity for self renewal adult MSCs may represent units of active regeneration of tissues damaged as a result of disease. In certain degenerative diseases such as osteoarthritis (OA) MSCs are depleted, and have reduced proliferative capacity and reduced ability to differentiate. The delivery of MSCs to these patients may therefore increase repair or inhibit the progressive destruction of the joint. Delivering MSC preparations to the osteoarthritic joint we could stimulate regeneration of cartilage and retard the progressive destruction of the joint.

The purpose of this review article is to summarize the existing knowledge on the role of autologous mesenchymal stem cells (MSCs) in the treatment of knee OA based on the studies published in PubMed and the Cochrane Library, and to make a rigorous review of the methodology and results of the various animal and clinical studies published so far on the topic.


METHODS
A review has been performed on role of intra-articular injections of autologous MSCs in patients with knee OA. The search engine was MedLine (PubMed) and the Cochrane Library. The keywords used were: stem cells and knee osteoarthritis. One hundred and twenty-three articles were found, but only sixteen were selected and reviewed because they were deeply focused on the topic.


RESULTS

EXPERIMENTAL STUDIES
In 2003 Murphy et al [3] explored the role that implanted MSCs may play in tissue repair or regeneration of the knee joint, by delivery of an autologous preparation of MSCs to caprine knee joints following induction of OA. Local delivery of adult MSCs to the joints retarded the progressive destruction of the joint.
In 2008 Al Faqueh et al [4] studied if autologous bone marrow MSCs cultured in chondrogenic medium could repair surgically induced OA in a sheep model. Their results indicated that knee joints treated with autologous bone marrow MSCs cultured in chondrogenic medium showed clear evidence of articular cartilage regeneration.
In 2009 Grigolo et al [5] performed an experimental animal study of OA in rabbits. They demonstrated that Hyaff-11, a hyaluronan-based scaffold, has potential for MSC implantation and that may have application for the treatment of early OA in humans.
In 2011Toghraie et al [6] used scaffold free MSCs obtained from infrapatellar fat pad in an experimental rabbit model of OA by direct intra-articular injection. They stated that, infrapatellar fat pad derived MSCs could be the promising cell sources for the treatment of OA.
In 2012 Sato et al [7] tested the outcome of intra-articular transplantation of MSC suspended in hyaluronic acid (HA) in the knee joints of guinea pigs with spontaneous OA. Their findings suggested that intra-articular injection of HA-MSC mixture was potentially beneficial for OA.
In 2012 Suhaeb et al [8] analyzed the effects of MSCs, hyaluronic acid (HA) and the combination of HA-MSC in treating OA in a rat model. The study suggested that the use of either HA or MSCs effectively reduced OA progression better than their combined use.
In 2012 Al Faqeh et al [9] studied whether or not an intra-articular injection of a single dose of autologous chondrogenic induced bone marrow MSC could retard the progressive destruction of cartilage in a surgically induced OA in sheep. They stated that the intra-articular injection of a single dose of bone marrow MSC either chondrogenically induced or not, could retard the progression of OA in a sheep model.
In 2012 Toghraie et al [10] induced OA in adult white New Zealand rabbits by unilateral anterior cruciate ligament transection. The study suggested that ASCs obtained from subcutaneous adipose tissue could be a viable approach for treating OA.
In 2012 ter Huurne et al [11] explored the effect of intra-articular injection of ASCs on synovial lining thickness and its relation to joint pathology in experimental mouse OA. The findings indicated that a single injection of ASCs into the knee joints of mice with early-stage collagenase-induced OA inhibits cartilage destruction.
HUMAN STUDIES
In 2012 Varma et al [12] studied 50 patients with mild to moderate knee OA. The patients were divided in two groups (group A and group B). Group A received arthroscopic debridement alone and group B received MSC concentrate injection along with the arthroscopic debridement of the knee. On follow-up, patients were evaluated on the basis of visual analogue scale (VAS) score and OA outcome score. The results suggested that the technique considerably improved the overall OA outcome score, especially the quality of life within the studied follow-up period and at the end of the follow-up. This study is the only one on the topic that has been included in the Cochrane Library so far.
In 2012 Koh et al [13] analyzed twenty five infrapatellar fat-pad-derived MSC injections combined with arthroscopic debridement that were administered to patients with knee OA. A mean of 1.89 � 10(6) MSCs were prepared with approximately 3 mL of platelet-rich plasma (PRP) and injected in the selected knees of patients in the study group. The mean Lysholm, Tegner activity scale, and VAS scores of patients in the study group improved significantly by the last follow-up visit. No major adverse events related to the injections were found during the treatment and follow-up periods. The results were compared between the study and control groups, in which the patients had undergone arthroscopic debridement and PRP injection without stem cells. Although the preoperative mean Lysholm, Tegner activity scale, and VAS scores of the study group were significantly poorer than those of the control group, the clinical results at the last follow-up visit were similar and not significantly different between the two groups. The short-term results of this study were encouraging and demonstrated that infrapatellar fat pad-derived MSC therapy with intra-articular injections was safe, and provided assistance in reducing pain and improving function in patients with knee OA.
In 2013 Koh et al [14] evaluated the clinical and imaging results of patients who received intra-articular injections of autologous MSCs for the treatment of knee OA in a therapeutic case series. The study group comprised 18 patients (6 men and 12 women), among whom the mean age was 54.6 years (range, 41 to 69 years). In each patient the adipose synovium was harvested from the inner side of the infrapatellar fat pad by skin incision extension at the arthroscopic lateral portal site after the patient underwent arthroscopic debridement. After stem cells were isolated, a mean of 1.18�� 10(6) stem cells (range, 0.3�� 10(6) to 2.7�� 10(6) stem cells) were prepared with approximately 3 mL of platelet-rich plasma (with a mean of 1.28�� 10(6) platelets per microliter) and injected into the selected knees of patients. Clinical outcome was evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index, the Lysholm score, and the visual analog scale (VAS) for grading knee pain. The results of this study were encouraging and showed that intra-articular injections of infrapatellar fat pad-derived MSCs was effective for reducing pain and improving knee function in patients with knee OA.
Twelve patients with chronic knee pain unresponsive to conservative treatments and radiologic evidence of OA were treated by Orozco et al in 2013 [15]. They used autologous expanded bone marrow MSCs by intra-articular injection (40�10 cells). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. The authors concluded that the intervention was simple, did not require hospitalization or surgery, provided pain relief, and significantly improved cartilage quality.
DISCUSSION
OA, a prevalent chronic condition with a striking impact on quality of life, represents an enormous societal burden. Yet no approved procedure prevents the progressive destruction of the OA joint. Local delivery (intra-articular injections) of ex vivo cultures of autologous MSCs has produced promising outcomes in experimental models of joint disease [1-11]. 
Mesenchymal stem cells (MSCs) have the capacity to differentiate into a variety of connective tissue cells including cartilage. These multipotent cells have been isolated from bone marrow and from other adult tissues including skeletal muscle, fat and synovium. Delivering MSC preparations to the injured knee joint we could stimulate regeneration of cartilage and retard the progressive destruction of the joint [1] [2].
Only three low-quality clinical studies have been reported so far on the role of MSCs injections in knee OA. Study design weakness prevents effective comparison of the efficacy of MSC injections with that of other treatments for relief of pain and other outcomes in knee OA. The consistency of evidence of the clinical studies is low because of many uncontrolled variables [16].

In conclusion, thirteen experimental studies suggest that intra-articular injections of autologous MSCs can have the potential to promote cartilage regeneration in knee OA. Taking into account the low quality of the data reported in clinical studies, my conclusion is that intra-articular injections of autologous MSCs in knee OA is a treatment that is still experimental.
REFERENCES
1.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Barry%20F%5BAuthor%5D&cauthor=true&cauthor_uid=23881068" Barry F,  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Murphy%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23881068" Murphy M (2013) Mesenchymal stem cells in joint disease and repair.  HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/23881068" \o "Nature reviews. Rheumatology." Nat Rev Rheumatol. 2013 Jul 23. doi: 10.1038/nrrheum.2013.109. [Epub ahead of print]
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