Paper:
Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial
PDF of the article reviewed is available here
Introduction to Osteoarthritis and Study Purpose
Knee
osteoarthritis is the most common form of arthritis, a connective tissue
disorder causing pain, stiffness, and decreased mobility. Osteoarthritis is one
of the leading causes of disability among adults, and as such, trials are
always ongoing, attempting to find different methods to treat this debilitating
disorder. At present, more than 50 forms of treatment – pharmacological,
non-pharmacological, and surgical – exist to treat the different aspects of
arthritis, most with only moderate success, and none are cures for the
disorder.
Osteoarthritis
is characterized by degeneration of articular cartilage, cartilage that lines
moveable joints within the body. This is shown in Figure 1. As the cartilage degenerates, bones begin to
rub together, causing the immense pain the disorder brings. Methods of
treatment in previous years have begun to focus on ways to regenerate this
cartilage that has been lost, especially through the use of cell therapy and
tissue engineering. These methods, though, have largely been of no clinical
benefit.
Figure 1. Overview of knee osteoarthritis. Retrieved from http://www.aihw.gov.au/osteoarthritis/what-is-osteoarthritis/
This
study uses mesenchymal stem cells (referred to as MSCs from here) to attempt to
regenerate articular cartilage in patients with osteoarthritis in the knee. No
clinical trials have been conducted that have used MSCs for this purpose, and
only a few case studies using this method have been reported. This study is the
first to enter the proof-of-concept phase of a clinical trial using this method
for the treatment of knee osteoarthritis.
General Materials and Methods
To deliver the MSCs to the appropriate
region, a single orthopedic surgeon completed direct injection into the joint,
ensuring consistency in the delivery method. Patients were assigned to either a
low-, mid-, or high-dose group, receiving incremental concentrations of MSCs in
their injections. All other medications, with the exception of rescue analgesic
and acetaminophen, were discontinued in order to ensure any significant results
were due to the treatment.
Patients
enrolled in the study were followed up with at 1, 2, 3, and 6 months
post-injection. At these visits, MRIs were taken, arthroscopies were performed,
and a biopsies of the cartilage affected were taken. These samples were later
used and analyzed to determine MSC injection success.
Results
Clinical Results
Improvements were seen in trial
participants who received a high dose of MSCs, whereas no improvements were
seen in trial participants receiving a low or medium dose of MSCs. Figure 2 shows the WOMAC score (Western Ontario and McMaster Universities
Osteoarthritis Index) of each of the dose-groups
through the months of the study. The WOMAC score is used to evaluate conditions
of patients with osteoarthritis, and as such, is a good measure of the
improvement, or lack thereof, that this treatment provides. Improvements were
only statistically significant in patients in the high-dose group.
Figure 2. WOMAC scores of low-, mid-, and high-dose groups in response to mesenchymal stem cell injection into the knee
Radiological Outcomes
Using MRI, the size of the cartilage defect in
each of the patients could be analyzed throughout the trial. The size of the
defect significantly decreased in patients in the high-dose of MSCs groups,
whereas those in the low- and medium-dose groups showed no significant changes.
The MRIs of two patients in the high-dose group are shown in Figure 3, and
Figure 4 summarizes the change in defect size for the three groups over time.
Figure 3. MRI scans of two patients in the high-dose of MSCs group, showing a decrease in cartilage defect size from the initial time and 6 months post-injection
Figure 4. Change in cartilage defect size on medial femoral condyle and medial tibial condyle of the knee after treatment with differing doses of mesenchymal stem cells
Histological Outcomes
Biopsy specimens taken before injection with
MSCs were shown to have no articular cartilage, as shown in Figure 5 (top row of sections). At six
months post-injection, articular cartilage was regenerated. The articular
cartilage had a thick and glossy white matrix and a smooth surface that became
well integrated in the bone layer immediately next to the cartilage. Specific
stains were used to determine the composition of the regenerated cartilage, and
collagen types 1 and 2 were found in different sections of the cartilage, also as shown in figure 5 (bottom row of sections). Histological analysis also showed that chondrocytes were
present in the calcified cartilage zone.
Figure 5. Histological analysis of a patient in the high-dose of MSCs group showing regeneration of cartilage from the baseline time point to 6 months post-injection
Discussion
The results of this study indicate that
high-doses of mesenchymal stem cells injected into the knee are able to
regenerate articular cartilage lost through the osteoarthritis. High-doses of
MSCs also resulted in clinically meaningful pain reduction in patients. These
conclusions show that this treatment method could potentially be used for
clinical treatment of osteoarthritis.
Histological analysis revealed that the
regenerated cartilage was well integrated into the subchondral bone. Both
hyaline cartilage (collagen II) and fibrocartilage (collagen I) were identified
in the regenerated cartilage, showing that the MSCs were successful in differentiating
into articular cartilage.
In
osteoarthritis, MSCs are depleted and also have reduced proliferative capacity
and a reduced capacity to differentiate. In providing MSCs through injections,
this reduction could be counteracted, allowing for the growth of articular
cartilage. The exact mechanism through which MSCs regenerate articular
cartilage is not known, but various hypotheses exist; this could be examined in
later studies.
Critique and Future Directions
I thoroughly enjoyed this paper and the
clinical trial that was conducted. The results found in this trial indicate
that mesenchymal stem cells injected into the knee could have regenerative
effects in those with osteoarthritis, and this is a huge step forward in the
treatment of these types of diseases.
The
experiments that were conducted, in my eyes, were quite thorough in that they
used multiple techniques to determine whether or not cartilage was being
regenerated. One critique I have on the methods is that they could have used
more subjects. Further to that, this was only an initial clinical trial into
this method of treatment, and subsequent clinical trials will probably enlist
more patients, making the results more reliable.
A
second critique I have of the methods is the time frame of the study. The final
sampling time for MRI, arthroscopic, and histological analysis was only six
months post-injection. In extending the period of study, I feel that they their
results could have been even more substantial, especially in the group that
received a high-dose of MSCs.
I
think some more background into osteoarthritis, and bone degenerative diseases
as a whole, could have been given in the introduction. This would have helped
more clearly state the purpose of the study and how the MSCs could potentially
have a positive effect. This background was later given in the discussion when
helping to explain the results, but probably could have been better suited in
the intro.
Citation:
Jo, C.H., Lee, Y.G., Shin, W.H., Kim, H., Chai, J.W., et al. (2014). Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of- concept clinical trial. Stem Cells. 32(5):1254-1266.
