Table 2 Main signaling pathways in cartilage regeneration

Notch

Notch signaling contributes to vertebrate development [78]. Its activation and expression exhibit a fluctuant pattern throughout chondrocyte maturation and display a dual function: sustained Notch activation in joint cartilage leads to an OA-like pathology, while transient activation could achieve increased cartilage ECM synthesis and successful joint maintenance [79, 80]

Intra-articular injection of BMP9 transfected AT-MSCs enhanced type II collagen and aggrecan expression and promoted cartilage repair through Notch1/Jagged1 signaling pathway in mouse knee OA model [81]

Micro ribonucleic acid (miR9) promoted the differentiation of chondrocyte and cartilage regeneration in the rabbit OA model by mediating type II collagen expression via the down-regulation of the Notch signaling pathway [82]

Wnt

Wnt signaling contributes to skeletal development and growth [83]. Wnts and MITF signaling pathways are responsible for the generation of off-target differentiation into neural cells and melanocytes during chondrogenesis of iPSCs [84]

A synthetic Wnt5a (non-canonical) mimetic ligand, Foxy5 peptide, was conjugated to hyaluronic acid hydrogel to enhance chondrogenic expression of MSCs and cartilage regeneration in subcutaneous pockets on the back of mouse [85]

Down-regulation of the Wnt transduction produced better quality articular cartilage-like tissue by MSCs cultured in faster degrading and soft matrices, which were implanted in subcutaneous pockets of mice [86]

Injection of SM04690 upregulated Wnt16 expression and therefore ameliorated abnormal subchondral bone remodeling in both rabbit and rat models and enhanced chondrogenesis of fibrocartilage stem cells [87]

TGF-β/BMP

The TGF-β superfamily is consisted of over 40 members that are classified into TGF-β and BMP subfamilies [88]. They play crucial roles in regulating condensation, cell survival and differentiation [89]

Autogenous platelet-rich-plasma treated BM-MSCs-seeded collagen scaffolds indicated accelerated cartilage regeneration through TGF/SMAD pathway in rabbits [90]

Naringin-treated BM-MSCs demonstrated an efficient articular cartilage repair in rabbit knees through activation and continuous regulation of the TGF-β superfamily pathways [91]

TGF-β1 transfected BM-MSCs seeded in calcium alginate gel improved the repair of rat cartilage defect through canonical SMAD2/3 signaling pathway and inhibited chondrocyte hypertrophy by decreasing hypertrophy makers expression via Hippo pathway [92]

NF-κB

Transcription factor NF-κB is a master regulator of inflammation involved in the pathogenesis and progression of OA [93]. In its inactive state, NF-κB presents in the cytoplasm as a heterotrimer complex and is prevented from entering nuclei; while chondrocytes are stimulated, NF-κB can be released and activated from IκB through degradation and enter nuclei [94]. Therefore, stopping the degradation of IκB could be an effective way to inhibit the NF-κB signaling pathway

Intra-articular injection of IGF-1 prevented the expression of MMPs and various apoptotic markers by inhibiting the NF-κB signaling and suppression of ROS production during OA pathogen and resulted in a better cartilage defect therapy in a rabbit knee OA model [95]

Bone defect was treated with anti-osteogenic reagents Fulvestrant and IL1β to inhibit ossification during cartilage regeneration by activating NF-κB signaling [96]

HIF

Articular cartilage survives in a microenvironment devoid of oxygen, which is controlled by HIF signaling [97, 98]. Overexpressing of HIF is clinically associated with OA [99]

3D-printed bioactive ceramic scaffolds containing Sr/Si or Li/Si or Cu ions stimulated cartilage and subchondral bone regeneration in rabbits by promoting chondrocytes maturation via activating HIF pathways [100,101,102]

IOX2, a HIF-1α prolyl hydroxylase domain inhibitor, was used to promote the proliferation and migration of BM-MSCs via stabilizing HIF-1α pathway and accelerating cartilage fracture healing in rats [103]

FGF

FGF signaling accelerates the termination rate of hypertrophic differentiation to help chondrocytes remain within cartilage rather than undergoing hypertrophic maturation prior to ossification [77]. It acts as an antagonist of BMP signaling, which hinders the termination of hypertrophic differentiation [104]

Pellets of MSCs cultured with FGF were implanted into osteochondral defects of mice to promote cartilage regeneration [105]

Sulfated alginate hydrogel was used to drive mitogenicity of chondrocytes, promote cartilage matrix production, and prevent chondrocyte dedifferentiation via the mediation of FGF signaling in a heparin-mimetic manner [106, 107]

IGF

IGF can influence metabolic and proliferative processes of cartilage and play a role in protection against ECM degradation [108, 109]. It regulates cartilage growth and homeostasis in TMJ fibrocartilage stem cells [110]

Platelet-derived biomaterial significantly suppressed OA-like pathophysiological characteristics by restoration levels of IGF-1 signaling pathway proteins [111]

Combined usage of IGF-1 and TGF-β1 in BM-MSCs-seeded laminin scaffolds enhanced the restoration of hyaline cartilage in a rabbit knee osteochondral defect model [112]