In this study, we used an ACLT + MMx OA model to evaluate the effect of KJD + MSCs intra-articular injection on OA. We found that KJD + MSCs injection can reduce secondary inflammation, cartilage degradation and irregular ossification of the subchondral bone effectively. Although in this experiment, KJD alone showed improvement over the non-treated OA group, combination therapy was significantly better than both. The mechanism is hypothesized to be due to joint distraction relieving aberrant mechanical stress and MSCs regulating the inflammation, allowing intrinsic tissue repair of the joint. Therefore, it is indicated that KJD combined with MSCs injection can achieve a mutually reinforcing therapeutic effect in OA treatment.
The therapy of young OA patients is a worldwide challenge. Younger patients have a high demand for joint functional activities, which will accelerate the wear of artificial joints. Second, most joint replacement patients face the problem of revision surgery due to the limitation of the service life of current joint prostheses. Therefore, clinical and basic researchers are trying to find alternative treatments for this group of patients. Since the first use of joint distraction in the treatment of arthritis, it has been considered an alternative treatment for younger patients with OA, and clinical and animal experiments have shown the advantages of this treatment approach. For example, Yang Xu et al. used joint distraction to treat severe traumatic ankle arthritis in patients with an average age of 30.3 ± 14.3 years. After treatment, the joint pain of the patients was relieved, and the joint space increased by three mm after one year. In our previous study of KJD in the rat OA model, we observed that the cartilage defect of the treated group was smaller than that of the control group, and the inflammatory factors and subchondral bone mineral density also were better than those of the control group. Therefore, we inferred that joint distraction could decelerate secondary inflammation, cartilage degeneration and subchondral sclerosis. However, in our previous study, we did not have a follow-up period, so we did not know how long the therapeutic effect lasted after joint distraction. To answer this question, in this study we defined a three week follow-up period after KJD treatment. Our results show that KJD + MSCs has a better therapeutic effect than KJD only or no treatment, as evidenced by the level of cartilage damage (Figs. 2–3), abnormal subchondral bone remodeling (Fig. 4) and secondary inflammation (Fig. 5). Our results are consistent with other research using KJD that this therapy can delay OA progression. We also found that the therapeutic effect is better when combined with MSCs, indicating that MSCs play an important role in regulating the micro-environment of the OA joint (Figs. 2–5).
MSCs are a kind of adult stem cell with multiple differentiation potential that can be isolated from various tissues such as bone marrow, adipose tissue, and synovium. MSC treatment of OA has been widely used in animal and clinical experiments. These experiments have demonstrated safety and are associated with cartilage regeneration, pain relief, and knee joint function improvement. Most of the experiments showed satisfactory results. According to previous experiments, it can be concluded that MSCs play a therapeutic role mainly through directional differentiation, regulation of immunity, and anti-inflammatory and exocrine effects[28–31]. For example, in a clinical study, published by our research team, we found that MSC injection treatment has a potential therapeutic effect for wrist OA, as shown by numerical improvement in performance and pain scores. In animal studies published by our research group, we found that MSCs that were pre-treated by chondrogenesis induction and differentiation and then reverse-differentiated into stem cells, had better therapeutic effects by relieving cartilage damage and subchondral sclerosis than in OA group or without pre-treated MSC treatment group[19, 20]. The articular cavity environment of patients with OA is different from that of normal people. Inflammatory factors (such as IL-1, TNF), pericellular matrix (such as hyaluronic acid concentration) and an extremely hypoxic environment affect the growth and function of MSCs[7, 32]. In the present study, we observed that KJD + MSCs had better results than the other groups (Figs. 2–5). Especially, we find that the number of CD68+ (macrophage marker) cells significantly decreased more in the affected joint in the KJD + MSCs group than in the other groups (Fig. 5). In this study, we did not find that MSCs directed differentiation to chondrocytes (data not shown). Taken together, we speculated that in this study, MSCs would play a role in the regulation of immunity, and have anti-inflammatory and exocrine effects, which combined with joint distraction would regulate the micro-environment of the OA joint, facilitating joint intrinsic repair (Figs. 2–5).
There are several mechanisms to explain the treatment of OA by joint distraction. First, the alignment of the joint is corrected to avoid compression of the damaged joint, which is conducive to the repair of the articular surface. Second, joint distraction can generate intermittent hydrostatic pressure, thus stimulating MSCs in the joint cavity to play a therapeutic role. However, the number of MSCs in the articular cavity is relatively small, and it is difficult to stimulate MSCs through joint distraction. Therefore, in current reports of joint distraction treatment of OA, the treatment time is usually longer than two months[25, 33]. In the natural progression of OA, a longer joint distraction cycle will shorten the interval between joint distraction and joint replacement. In order to shorten the joint distraction treatment cycle, in this experiment, we injected MSCs into the articular cavity to increase the number of MSCs. Even though the treatment period of this experiment was only three weeks, which is shorter than that of other experiments, the results showed that the combination KJD + MSCs therapy is better than KJD alone in slowing down the processes of secondary inflammation and subchondral sclerosis and so on (Figs. 2–5). This proves that intra-articular injection of MSCs enhances the therapeutic effect of KJD, and the combined treatment of MSC intra-articular injection and KJD has complementary effects.