5-HT Implicated in Regulation of Osteoclastogenesis in RA

HealthDay News –  Serotonin or 5-hydroxytryptamine (5-HT) plays a direct immunoregulatory role in the development of autoimmune arthritis, according to an experimental study published online March 8 in The American Journal of Pathology.

Yasmine Chabbi-Achengli, from the INSERM Unité Mixte de Recherche 1132 in Paris, and colleagues examined 5-HT involvement during collagen-induced arthritis in wild-type and Tph1^−/− mice that are genetically bred to have a deficiency in tryptophan hydroxylase-1, the enzyme responsible for peripheral 5-HT production.

The researchers found that induction of arthritis triggered a robust increase in 5-HT content in the paws and less inflammation than compared to wild-type mice. There was a marked increase observed in the clinical and pathologic arthritis scores in Tph1^−/− mice with arthritis.  

The number and activity of osteoclasts were higher in 5-HT-deficient mice with induced arthritis as compared to wildtype mice. In addition, more bone resorption was detected both at the affected joints and at remote sites.

Specifically, there was a significant increase in osteoclast differentiation and bone resorption with an increase in interleukin (IL)-17 noted in the paws and in the Th17 lymphocytes of the draining lymph nodes in Tph1^−/− mice; in contrast, T-regulatory cells were dampened. In Tph1^−/− mice, ex vivo 5-HT and agonists of the 5-HT2A and 5-HT2B receptors restored IL-17 secretion from splenocytes and Th17 cell differentiation.

Disruption in the balance between Th17 and Treg cells could be normalized by adding 5-HT or 5-HT receptor agonists in cell culture. 

“These findings indicate that 5-HT plays a fundamental role in arthritis through the regulation of the Th17/ T-regulatory cell balance and osteoclastogenesis,” the authors write.

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Summary and Clinical Applicability

This research found that in an experimental animal model 5-HT was involved in regulating the balance of helper T-cells resulting in modulation of osteoclastogenesis.  Although 5-HT is primarily known for its regulatory role in the central nervous system, this study found that mice with genetic inability to produce 5-HT in peripheral tissues had an increase in number and function of osteoclasts.   This indicates that 5-HT regulation may be disrupted in autoimmune arthritis leading to increased levels of bone resorption resulting from unbalanced osteoclastogenesis.

“5-HT deficient mice are characterized by a relative, dampened expansion of [regulatory T-cells] associated with an enhanced shift toward a Th17 phenotype, a situation previously described in patients with arthritis,” the authors of this study noted. 

If further validated, this study highlights the possibility of future RA treatments directed towards 5-HT or 5-HT receptors in regulating the inflammatory immune response.   

Reference

Chabbi-achengli Y, Coman T, Collet C, et al. Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption. Am J Pathol. 2016;