Background/Purpose:

Smoking is a major risk factor for the development of anti-citrullinated protein antibodies positive rheumatoid arthritis (RA) in individuals who carry shared epitope alleles. The molecular mechanisms that confer this risk are however not clarified up to now. Even more it is not clear whether smoking can affect joint physiology directly or via indirect immune mechanisms that cross-react with joint structures. We analyzed synovial tissues of human smokers and of mice exposed to cigarette smoke as well as in vitro stimulated RA synovial fibroblasts (SF) to find effects of smoking on joint physiology.

Methods:

Synovial tissues were obtained from smoking (n=5) and non smoking (n=6) RA patients undergoing joint replacement surgery and from mice exposed to cigarette smoke (n=6) or room air (n=8) or) in a whole body exposure chamber for 3 weeks. RASFs were incubated with 5% cigarette smoke extract (CSE) (n=7). Changes in gene expression were detected using whole genome microarrays and verified with Real-time PCR and immunoblotting.

Results:

Gene expression analysis and functional classification showed that CSE treatment in vitro leads to a broad activation of the chaperone and heat shock protein system. This finding could be confirmed in vivo, where we found a significant increase in the expression of the HSP40 family members, DnaJB4 (1.8 fold) and DnaJC6 (2.2 fold) in synovial tissues of human smokers as well as in mice exposed to cigarette smoke (DnaJB4 2.2 fold, DnaJC6 2.7 fold). Furthermore, in human synovial tissues, but not in mice, smokers had 3.5 fold higher levels of Hsp70 and 3.2 fold higher levels of HspB8 similar to what was seen in in vitro stimulations.

The list of CSE altered genes also contained a ligand of the activating immune receptor NKG2D. This ligand, MICB, together with other ligands of this receptor namely MICA, ULBP2 and ULBP3 was significantly increased after CSE in vitro. MICA (2.6 fold) and MICB (2.1 fold) were also significantly higher in synovial tissues of smokers compared to non-smokers. In addition the mouse homologue of these ligands, H60 was 2.9 fold higher expressed in joints of smoke exposed mice.

Conclusion:

Our results clearly show that systemic effects of cigarette smoke include changes in joints. Since synovial fluid is passively filtrated from the blood, it is feasible to assume that cigarette smoke components in the blood can reach the synovial fluid and influence local tissue physiology. Therefore smoking can increase the risk to develop RA by locally changing gene expression in the synovium.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effects-of-smoking-on-joint-physiology-in-men-and-mice/