Table 3.
Therapeutic reagents and their strategies and target genes have been reported for each OA pathogenic signaling pathway
| Signaling pathway | Key protein | Articular cartilage | Synovial membrane | Subchondral bone | Joint cavity (synovial fluid) | References |
|---|---|---|---|---|---|---|
| Wnt | Wnt | Increated in DMM-induced OA in mice; Increased in human OA cartilage | Increased in human OA cartilage | unknown | Increated in DMM-induced OA in mice; Increased in human OA cartilage | PMID: 22682243;27147711 |
| WISP-1 | Increased in human OA cartilage | Increased in human OA cartilage | Increased in human OA cartilage | Increased in human OA cartilage | PMID: 19180479 | |
| β-catenin | Increased in human OA cartilage | Increased in human OA cartilage | Increased in human OA cartilage | Increased in human OA cartilage | PMID: 19180479;15866164 | |
| Dickkopf-1 | unknown | unknown | unknown | Decreased in human OA cartilage | PMID: 28678406 | |
| AMPK pathway | AMPKα | Decreased in DMM-induced OA mouse model and Human knee OA chondrocytes. | Decreased in acute gouty arthritis (AGA) rats. | unknown | unknown |
PMID: 25940958;30585453 |
| AMPKβ | unknown | unknown | unknown | unknown | n.a | |
| AMPKγ | unknown | unknown | unknown | unknown | n.a | |
| NF-κB | RelA/p65 | P65 protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p65 translocates to the nucleus in human OA cartilage | P65 protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p66 translocates to the nucleus in human OA cartilage | P65 protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p67 translocates to the nucleus in human OA cartilage | P65 protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p68 translocates to the nucleus in human OA cartilage | PMID: 31842396 |
| RelB | RelB protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; RelB translocates to the nucleus in human OA cartilage | RelB protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; RelB translocates to the nucleus in human OA cartilage | RelB protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; RelB translocates to the nucleus in human OA cartilage | RelB protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; RelB translocates to the nucleus in human OA cartilage | PMID: 31842396 | |
| c-Rel | c-Rel protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; c-Rel translocate to the nucleus in human OA cartilage | c-Rel protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; c-Rel translocate to the nucleus in human OA cartilage | c-Rel protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; c-Rel translocate to the nucleus in human OA cartilage | c-Rel protein is released, phosphorylated, and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; c-Rel translocate to the nucleus in human OA cartilage | PMID: 31842396 | |
| NF-κB1/p105p50 | The precursor protein p105 opposed to degradation and release of active p50; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p50 translocate to the nucleus in human OA cartilage | The precursor protein p105 opposed to degradation and release of active p50; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p51 translocates to the nucleus in human OA cartilage | The precursor protein p105 opposed to degradation and release of active p50; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p52 translocates to the nucleus in human OA cartilage | The precursor protein p105 opposed to degradation and release of active p50; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p53 translocates to the nucleus in human OA cartilage | PMID: 31842396 | |
| NF-κB2/p100p52 | The precursor protein p100 opposed to degradation and release of active p52; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p52 translocates to the nucleus in human OA cartilage | The precursor protein p100 opposed to degradation and release of active p52; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice; p53 translocates to the nucleus in human OA cartilage | The precursor protein p100 opposed to degradation and release of active p52; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice p54 translocate to the nucleus in human OA cartilage | The precursor protein p100 opposed to degradation and release of active p52; p50 protein is released and translocated from the cytoplasm to the nucleus in DMM-induced OA in mice p55 translocate to the nucleus in human OA cartilage | PMID: 31842396 | |
| HIF pathway | HIF1a | Decreased in DMM-induced OA in mice; Increased in human OA cartilage. | Upregulated in MIA-induced KOA in rats. | Upregulated in osteoblasts in human OA subchondral bone. | Increased in human OA cartilage. | PMID: 27122313; 28123469 |
| HIF2a | Increased in STR/ort and DMM mouse OA model. Increased in human OA cartilage. | Unknown | Unknown | Unknown | PMID: 28123469; 24999110 | |
| HIF3a | Unknown | Unknown | Unknown | Unknown | ||
| mTOR | mTOR | Increased in DMM-induced OA in mice; Increased in human OA cartilage. | Unknown | No change | Unknown | PMID:24651621 |
| Focal adhesion pathway | Kindlin-2 | Highly expressed in healthy articular cartilage; Decreased in aged and OA cartilage | Unknown | Unknown | Unknown | https://www.nature.com/articles/s43587-021-00165-w |
| Talin | Decreased in human OA cartilage | Unknown | Unknown | Unknown | ||
| Vinculin | Decreased in human OA cartilage | Unknown | Unknown | Unknown | ||
| Integrin αVβ3 | Unknown | Elevated in synovial membrane in DMM mouse model. | Unknown | Unknown | PMID:31534047 | |
| Focal adhesion kinase | Unknown | Unknown | Elevated in subchondral bone in ACLT rat model. | Unknown | PMID:32324278 | |
| BMP pathway | BMP-2 | Increased in human OA cartilage; Down-regulated in DMM-induced OA in rats | Unknown | Increased in human OA cartilage; Increased in ACLT-induced OA in rats | Decreased in patients with OA | PMID: 35216203; 32290085; 29429984 |
| BMP-4 | Increased in human OA cartilage; downregulated in DMM-induced OA in rats | Unknown | Increased in human OA cartilage | Unknown | PMID: 35216203 | |
| BMP-6 | Upregulated in DMM-induced OA in rats | Unknown | Unknown | Unknown |
PMID: 34680516 |
|
| BMP-7 | Decreased in human OA cartilage; upregulated in DMM-induced OA in rats | Unknown | Unknown | Unknown | PMID: 29980690; 26010756 | |
| GDF-5 | Down-regulated in DMM-induced OA in rats | Unknown | Unknown | Unknown |
PMID: 26010756 |
FRZB frizzled-related protein, IκB inhibitors of NF-κB, IKK IκB kinases, HIF hypoxia-induced factor, PHD HIF prolyl hydroxylases, AAV adeno-associated virus