Aims: 

Tachykinins (substance P and neurokinin A) encoded by the preprotachykinin A (TAC1) gene predominantly in capsaicin-sensitive sensory neurones, are involved in inflammation and pain via neurokinin 1 and 2 (NK1, NK2) receptor activation, respectively. Hemokinin-1 (HK-1) derived from the TAC4 gene in inflammatory/immune cells and in the central nervous system also acts at NK1 receptors. We investigated chronic arthritis and osteoartritis in TAC1^-/-, TAC4^-/-, and NK1^-/- knockout mice compared to C57Bl/6 wildtype (WT) counterparts.

Methods: 

Chronic tibiotarsal joint inflammation was induced by injection of complete Freund's adjuvant (CFA) into the paw and tail root, osteoarthritis of the tibiofemoral joint by intraarticular sodium-monoiodoacetate (MIA). Paw volume was measured with plethysmometry, knee diameter with a digital micrometer, the mechanonociceptive threshold with dynamic plantar aesthesiometry throughout the 21-day experimental periods. Histopathological evaluation and semiquantitative scoring of the joints were also performed on the basis of characteristic inflammatory and degenerative parameters.

Results: 

No difference was found in TAC1^-/- mice in any measured parameters in either model. In the TAC4 and NK1 gene-deleted groups edema was not different, but hyperalgesia was significantly smaller in both models from day 11. Synovial enlargement, inflammatory cell infiltration and cartilage destruction in the CFA model were significantly less severe in the TAC4^-/- animals, but not in the other groups. Degenerative histopathological parameters were not influenced by the lack of these tachykinins and the NK1 receptor.

Conclusion: 

HK-1 encoded by the TAC4 gene enhances hyperalgesia in the late phase of chronic arthritis and osteoarthritis through NK1 receptor activation. It is likely to have different binding sites and signal transduction pathways than SP. HK-1 also aggravates the inflammatory histopathological parameters, but NK1 receptors are not involved in these actions. Therefore, a potential role of a putative HK receptor can be proposed in the joints.

Support: 

OTKA K73044, ETT 03-380/2009, SROP-4.2.1.B-10/2/KONV-2010-0002