Inhibition of bone morphogenetic protein 6 receptors ameliorates Sj\xf6gren\u2019s syndrome in mice

Hongen Yin,Paul B Yu,William D Swaim,Javier Cabrera-Perez,Arif Karim,John A Chiorini,Zhennan Lai,Sandra Afione,Lovika Kalra,Blake M Warner,Donald B Bloch,Alexandria Voigt,Nan Zhang,Cuong Q Nguyen,Maria C Guimaro,Lauren Aber,Drew Michael

doi:10.1038/s41598-020-59443-z

Abstract

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease, with only palliative treatments available. Recent work has suggested that increased bone morphogenetic protein 6 (BMP6) expression could alter cell signaling in the salivary gland (SG) and result in the associated salivary hypofunction. We examined the prevalence of elevated BMP6 expression in a large cohort of pSS patients and tested the therapeutic efficacy of BMP signaling inhibitors in two pSS animal models. Increased BMP6 expression was found in the SGs of 54% of pSS patients, and this increased expression was correlated with low unstimulated whole saliva flow rate. In mouse models of SS, inhibition of BMP6 signaling reduced phosphorylation of SMAD1/5/8 in the mouse submandibular glands, and led to a recovery of SG function and a decrease in inflammatory markers in the mice. The recovery of SG function after inhibition of BMP6 signaling suggests cellular plasticity within the salivary gland and a possibility for therapeutic intervention that can reverse the loss of function in pSS.

Highlights

Primary Sjögren’s syndrome is a chronic autoimmune disease that occurs predominately in women, with a female to male ratio of 9–16:11,2
The relationship between minor salivary gland (SG) bone morphogenetic protein 6 (BMP6) expression and two important SG-related manifestations of Primary Sjögren’s syndrome (pSS), SG dysfunction assessed by unstimulated whole saliva (UWS) flow rate and sialadenitis assessed by focus score (FS) or lymphocyte infiltration area was determined
These findings suggest that minor SG BMP6 expression is associated with the loss of SG function and with increased inflammation in pSS patients

Summary

Introduction

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that occurs predominately in women, with a female to male ratio of 9–16:11,2. Previous studies reported that expression of bone morphogenetic protein 6 (BMP6) is increased in the SGs of some pSS patients and that this overexpression is linked to a decrease in SG function and increased lymphocytic infiltration of the gland[3,4]. AQP1 gene therapy, does not correct all of the effects of increased expression of the BMP6 ligand that likely affects the activity of other cells in the gland, such as infiltrating lymphocytes and bone marrow mesenchymal stem cells[5,6]. The TGF-β cytokine superfamily is a group of 33 proteins, which include bone morphogenetic protein (BMP) and TGF members Members of this family bind to and signal through specific type I and type II transmembrane serine/threonine kinase receptor complexes. Some difference in activity exists between these inhibitors with LDN-212854 exhibiting greater selectivity towards ALK2 than ALK3 compared to LDN-19318913–15

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