Treating patients with OA presents a significant challenge for physicians as no therapies to date have demonstrated efficacy in curing or even halting disease progression. Therefore, most approaches initially target pain management and factors that may be exacerbating stress on the joint.
https://dx.doi.org/10.2147%2FSCCAA.S68073 – Mayo Clinic, MN
Corticosteroid toxicity for chondrocytes has been long reported, both for cartilage and tendons :
– https://www.ncbi.nlm.nih.gov/pubmed/15885481 ;
The efficacy of arthroscopic procedures are extensively debated since the study published in 2002 in The New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa013259). The complete inefficiency was confirmed by the most recent randomized controlled study published in 2017:
MSCs could provide an ideal source for direct regeneration of joint surfaces. While stem cells can both differentiate into new cartilage cells as well as suppress inflammation, recent studies have found that stem cells can also combat OA through paracrine mechanisms. They release important cytokines such as epidermal growth factor (EGF), transforming growth factor beta (TGFB), vascular endothelial growth factor (VEGF), as well as other cytokines and new cartilage proteins that are essential in combating OA and degenerative processes. It has also been suggested that stem cells could release cytokines and proteins that could help combat neurogenic pain, which would have numerous benefits in treating OA pain :
– https://www.ncbi.nlm.nih.gov/pubmed/23881068 ;
– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880954/ ;
– https://www.ncbi.nlm.nih.gov/pubmed/25512139 .
Regeneration of joint tissues has been documented after injection of MSCs; however, some studies have found that reconstitution of tissue is primarily from native cells and relatively few transplanted cells :
Other studies have shown that the cell signaling milieu is altered after the administration of MSCs with a subsequent increase in Type II collagen production by the host (https://www.ncbi.nlm.nih.gov/pubmed/22750747). Together, these factors suggest that MSCs may be orchestrating the reparative response rather than directly replacing damaged areas. This is in line with the well-documented anti-inflammatory and immunomodulatory role of MSCs (https://www.ncbi.nlm.nih.gov/pubmed/25426250). One of the breakthrough studies recently published has clearly demonstrated the attachment of MSCs to the full-thickness cartilage defects in rat models. Furthermore, these cells were found in abundance in the defect area 28 days after injection. What is intriguing is that the cells did not participate directly in the regeneration of the host cartilage in the long run since no tracking markers were observed 6 months following the injection.
The study concluded that MSCs did not give rise to new chondrocytes for long-term regeneration and the paracrine effect played a major role in the recruitment of the host regenerative capabilities (https://insight.jci.org/articles/view/87322).
Adipose stem cells/adipose-derived stromal cells (ASCs) have gained attention due to their abundance, excellent proliferative potential, and minimal morbidity during harvest. Adipose-derived mesenchymal stem cells (ADSCs) can be harvested from the patient’s own adipose tissue via surgical liposuction. These advantages lower the cost of cell therapy by alleviating the time-consuming procedure of culture expansion :
ADSC therapy for OA in animal studies is well documented (https://www.ncbi.nlm.nih.gov/pubmed/26987846). Toghraie et al. demonstrated that ADSCs derived from IFPs in rabbits given to rabbits with OA-induced knees had less cartilage destruction, less subchondral sclerosis, less osteophyte buildup, as well as better cartilage overall than the control group (https://www.ncbi.nlm.nih.gov/pubmed/20591677). It also was demonstrated that autologous ADSC therapy decreased the progression of degeneration in cartilage and in the synovial membrane, improving meniscal repair. The regenerative effect of autologous ADSCs is dose and time-dependent (https://www.ncbi.nlm.nih.gov/pubmed/23360790). Another group also reported cartilage regeneration following autologous ADSC therapy in a surgically induced osteoarthritic sheep model. Autologous ADSCs were labeled and intra-articularly injected, leading to the cells populating the area of damaged cartilage as well as a decreased progression of OA : https://www.ncbi.nlm.nih.gov/pubmed/24911365
Several clinical studies also prove ADSCs’ efficacy in treating OA in human patients. Koh et al. treated patients with knee OA undergoing arthroscopic debridement with injected autologous ADSCs derived from IFPs and prepared in platelet-rich plasma (PRP). Treated patients demonstrated improved mobility and function in the affected knees, reduced pain levels, and better clinical prognoses in a 1-year follow-up:
Some authors found the patients had significantly improved Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain scores, VAS pain scores, and cartilage regeneration as confirmed by MRI following 2 years of follow-up: https://www.ncbi.nlm.nih.gov/pubmed/23375182
In a different proof-of-concept clinical trial, autologous ADSCs were injected in patients with knee OA. The high-dose injection group had increased WOMAC scores 6 months after injections, decreased cartilage defects in affected areas, and increased cartilage volumes with thick, hyaline cartilage-like regeneration (https://www.ncbi.nlm.nih.gov/pubmed/24449146).
In 2011, Pak demonstrated the potential of ADSCs in osteonecrosis of the hip and OA in the knees of several patients. Results revealed bone formation in the osteonecrosis patients as well as cartilage regeneration in the OA knee patients. These patients’ MRIs had increased meniscus cartilage volume and thickness due to the ADSCs injections (https://www.ncbi.nlm.nih.gov/pubmed/21736710).
These results further proved the promising efficacy of autologous ADSCs in treating OA in humans, as well as demonstrated its safety as there were no adverse events. More similar clinical trials are necessary to further prove ADSCs’ efficacy for routine use in the human OA setting and more precisely define the mechanism of action. Last, but not least, it has been very recently documented that stem cells help dying or damaged cells by “recharging their mitochondrial batteries” in different organs, including joints:
– https://peerj.com/articles/3468/ .
In a degenerative joint, the mitochondria have been extensively exhausted and this reduces the functionality of cells. Healthy stem cells that have been injected into the affected joint, can rejuvenate damaged cells by transferring their “fully charged” mitochondrial batteries into the damaged cells. This final step completes a cascade of events that take place in the osteoarthritic joint (http://docplayer.net/21035327-Role-of-mitochondria-in-mesenchymal-stem-cells.html). The inactivation of the macrophages and the secretion of “helper” growth factors explain the long-term anti-inflammatory effect seen particularly with a stromal vascular fraction (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296619/). This mechanism of action shows how stem cells may decrease pain and swelling. The above model also suggests that stem cells have a disease-modifying effect, by restoring the balance of cells within the joint: there is an increase in the number of “facilitating” stem cells and a decrease in the number of “destructive” macrophages, reducing this way the self-destruction of the joint.
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