In our study, we successfully established a experimental model of TD in growing rats after patellar instability which was characterized by subchondral bone loss and cartilage degeneration and aggravated with time. Most importantly, remarkably increased expression of PI3K/AKT at protein and mRNA levels were discovered in the cartilage degeneration, revealed that the cartilage degeneration of TD might be associated with the activation of PI3K/AKT signal pathway. As far as we know, this was the first report on the relationship between PI3K/AKT and cartilage degeneration in the TD model of patellar instability.
As we all know, mechanical stress is one of the most major factors influencing the development of bone and cartilage [29]. Changing stress distribution of patellofemoral joint will affect the metabolism of cartilage and mismatch between the position of patella and femoral trochlear may lead to OA [30–32]. When the pressure of patellofemoral joint increases due to the abnormal biomechanics of patella, cartilage will be damaged more easily [33–34]. The present study supports the view that, the TD may be induced by mechanical stimuli since the pressure changes in the patellofemoral joint as a result of patellar instability and further aggravate withtime during the progression of TD. However, mechanical factors may not be the unique cause for TD to develop into OA. Because TD is a developmental disease, abnormal development of joints may lead to early articular cartilage degeneration.
The Pl3K/ AKT signal pathway is one of the key links in cell development, including cell metabolism, apoptosis, transcription and cell cycle [35]. At the same time, abnormal expressions of Pl3K/ AKT in many cancers were found in published papers [36]. Previous researches have shown that Pl3K/ AKT plays an significant role in the pathogenesis of OA [37, 38]. And inhibition of Pl3K/ AKT expression in rat chondrocytes can improve autophagy and delay the progression of OA [39, 40]. As we all know that the progression of OA is affected by inflammatory cytokines, and Pl3K/AKT signal pathway can mediate the NF-kB’s activation and the mRNA expression of TNF-a in osteoblasts, inhibition of Pl3K/AKT can protect chondrocytes from the disruption of inflammation in OA [41–44]. Based on the above testimony, we can assume that Pl3K/AKT signal pathway may play a very important role in TD pathological process. To test the hypothesis, we detected Pl3K/AKT in the trochlear cartilage of rats. The results of immunohistochemistry and mRNA showed that the expression of Pl3K/AKT increased with time in the TD model induced by patellar instability. Thus, the continuous high expression of Pl3K/AKT in the TD model may be one of the reasons for the continued existence of development factors in articular cartilage. However, further studies is needed to clarify how Pl3K / AKT plays a role in the pathological process of TD.
It is well known that TGF-β1 as an important research object in the future, its potential can be used clinically, thereby helping the diagnosis and treatment of OA [45]. Abnormally increased TGF-β1 in cartilage can promote the production of proteoglycans and lead to abnormal growth of osteophytes and synovium [46]. The TGF-β1 accelerrates the condensation of mesenchymal stem cells, and improves the early period of chondrocyte differentiation,yet inhibit the terminal hypertrophic differentiation too, so influcing the regular bone morphology [47]. In the present study, continued high expression of TGF-β1 in the TD model increased in a age-dependent manner. In general, these findings suggested that the articular cartilage in the rats TD model was consistent with the early molecular expression of OA.
In addition, our previous study has confirmed that TD can lead to cartilage degeneration [24, 25]. In present study, we found that with the increase of age, the morphology of cartilage in the rats of TD model changed, the surface of cartilage became rough, the vertical cracks appeared, and the articular chondrocytes aggregated. Furthermore, qRT-PCR showed that ADAMTS-4 [48], a marker of cartilage degeneration, was over expressed in the cartilage of TD model. Consequently, this research confirmed the cartilage degeneration in TD model. These findings were consistent with the manifestation of OA, suggesting that TD may be an important cause of patellofemoral OA.
Our study have several limitations. First, using the rat model is hard to straightly incarnate the real clinical situation. Second, this research only showed the early stage of patellofemoral OA at 12 weeks after patellar instability, and lacked experimental model data for long-term follow-up. Third, we demand to further investigate the molecular mechanism of PI3K/AKT signal pathway on cartilage degeneration of TD at the cellular level.