FGF18, which is an important growth factor, regulates osteogenesis and chondrogenesis during both embryogenesis and postnatal development. Previous studies have shown that Fgf18−/− mice have an increase in chondrocyte numbers and enhanced collagen production [9]. Recently, increasing evidence has indicated that FGF18 may play a positive role in chondrogenesis progression. It has been found that FGF18 can increase the number of chondrocytes and greatly reduce the loss of mucopolysaccharides in mouse arthrodial cartilage [17]. With increasing FGF18 concentration, the abnormal morphology (flattened, fusiform) of arthritis chondrocytes can gradually become a normal circle [18]. In this study, we isolated chondrocyte progenitors from newborn condylar cartilage, and infected these cells with Ad-FGF18. The differentiation of chondrocytes was promoted by FGF18, as proven by Alcian blue staining and the indicated cartilage differentiation markers.
OA is characterized by increased catabolic activity of chondrocytes, accompanied by cartilage degradation and inappropriate repair reactions. The earliest changes caused by OA included tissue fibrosis and joint surface wear [19], while the late stage was characterized by pathological changes in all tissues around the joint [20]. At present, drug treatments for OA, such as acetaminophen, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, and intra-articular corticosteroid injection [21], can only relieve symptoms, but cannot control the disease process. Surgical treatments such as autologous cartilage implantation, osteochondral transplantation and microfracture techniques have been applied to cartilage regeneration, but these surgical methods still hinder the repair of cartilage tissue and function [22]. Therefore, OA urgently needs novel therapies that are not limited to alleviating symptoms, but rather can interfere with disease progression. For example, osteoarthritis disease modifiers, which can prevent cartilage damage (anti-decomposition pathway) during joint disorder, can also promote tissue regeneration (synthetic pathway). Previously, our study showed that FGF18 plays a positive role in regulating the differentiation of chondrocytes. We next sought to investigate whether OA could be cured by FGF18. We performed DMM model operation on mice and injected Ad-FGF18 into their joint cavity.
We found that mice injected with Ad-FGF18 showed significantly decreased osteoarthritic cartilage destruction, as determined by SO staining and OSRSI score. The results of IHC staining showed that the expression of FGF18 was significantly increased in the cartilage of mice injected with Ad-FGF18. In addition, the expression of COL2 and ACAN in the cartilage of mice injected with Ad-FGF18 increased, and the expression of ADAMTS5 and MMP13 decreased. Collagen type II and aggrecan are the main components of the extracellular matrix of cartilage, and their loss is a necessary condition for the occurrence of OA. As a necessary factor for chondrogenesis, type II collagen accounts for 90% of the collagen content of cartilage. Type II collagenase displayed higher expression levels in the cartilage of OA mice [23]. Aggrecan, which determines the ability of the extracellular matrix to load pressure, is an early pathophysiological marker of OA [24]. MMPs and ADAMTSs can mediate the degradation of extracellular matrix and lead to cartilage loss of integrity. Their expression is upregulated in OA joint tissue and is directly involved in the pathophysiological process of OA [25]. MMP13 is a collagenase and directly degrades collagen type II and aggrecan in cartilage during the pathological process of OA [26]. Clinical studies have shown that MMP13 is highly expressed in the chondrocytes of OA patients [27]. Animal studies have also found that the overexpression of MMP13 in articular cartilage can induce an OA-like phenotype [28]. ADAMTSs can disrupt the balance of matrix synthesis and degradation and promote the hydrolysis of the aggrecan protein. Deletion of the Adamts-5 gene has a protective effect on cartilage degeneration [24]. Therefore, FGF18 may play a protective role in OA cartilage destruction.