Table 1.
Putative innate immune targets showing disease modification in preclinical studies
| Target tested | Study details | Cartilage modifying? | Symptom modifying? | |
|---|---|---|---|---|
| Complement | ||||
| Wang et al62 | C5 and Cd59a | Knockout data confirmed by pharmacological approach | Yes | Not examined |
| Chemokines | ||||
| Miotla Zarebska et al,63 Miller et al,64 Raghu et al,65 Longobardi,66 and Appleton et al67 | Ccl2 or Ccr2 | Constitutive gene deletion inconsistent across different studies but appearing to show structure modification at later time points; pharmacological studies point towards a key treatment window | Inconsistent | Yes |
| Takebe et al,68 and Raghu et al65 | Ccr5 or Ccl5 | Inconsistent cartilage degradation scores; neither study showed a difference in synovitis scores after gene deletion | Inconsistent | Not examined |
| Sambamurthy et al69 | Ccr7 | Modest structural role, knockout mice have reduced pain behaviour | Yes | Yes |
| Sherwood et al70 | Cxcr2 | Structural increase at 8 weeks in knockout mice (ie, protective) | Yes | Not examined |
| Qin et al71 | Cxcr4 | Inhibition in bone abrogates surgically induced osteoarthritis | Yes | Not examined |
| Mechanoflammation | ||||
| Choi et al72 | IkB-zeta subunit of Nf-κB | Over-expression worsens disease; conditional detection leads to decreased disease (both on Col2 promoter) | Yes | Not examined |
| Kobayashi et al73 | RelA (p65) Nf-κB transcription factor | Dual action of RelA in disease: heterozygotes protected; homozygotes showed increased disease through prevention of anti-apoptotic mechanisms induced by Pik3r1 (a Gwas hit for cartilage thickness) | Yes | Not examined |
| Culley et al74 | Ikka | Conditional knockout (aggrecan Cre) disease protection associated with increased apoptosis | Yes | Not examined |
| Ismail et al75 | Jnk2 | Chondroprotection observed at 4 weeks, 8 weeks, and 12 weeks after surgery | Yes | Not examined |
| Mast-cell activation | ||||
| Wang et al76 | c-Kit and Mcl1 | Deletion produces functional deletion of c-Kit-dependent and c-Kit-independent mast cells; chondroprotection also observed with Apc366, a tryptase inhibitor | Yes | Not examined |
| Wang et al76 | Igh7 and Fcer1 | Both genes target IgE-mediated activation of mast cells, indicating that IgE-induced mast-cell activation drives osteoarthritis pathology | Yes | Not examined |