Session Type: ACR Concurrent Abstract Session
Session Time: 11:00AM-12:30PM
Background/Purpose: Bone morphogenetic protein 6 (BMP6) plays a critical mechanistic role in decreasing salivary gland dysfunction in primary Sjögren’s syndrome (pSS) patients. Elevated BMP6 expression is associated with a loss of membrane water permeability and loss of gland function that is independent of inflammatory cell infiltration within the gland. The downstream signals activated by BMP6, which ultimately result in decreased salivary flow, are still unknown. BMP6 signals through type 1 receptors, which results in phosphorylation of SMAD1/5/8 transcription factors that ultimately alter gene expression within the nucleus. Two inhibitors,LDN-212854 and LDN-193189, have been developed to selectively target the ALK2 and ALK3 BMP type 1 receptors. This study examined the ability of these inhibitors to block BMP6 signaling, and their effect on expression of key proteins involved in salivary gland function and inflammation. We also investigated the ability of these inhibitors to restore salivary gland function in vivo.
Methods: BMP6 expression was detected in minor salivary glands (MSG) from N=80 pSS female patients (49.6 years old, range (21-74)) by immunofluorescent staining and quantified using Velocity software. Immunofluorescent staining was also used to confirm the presence of type I BMP6 receptors in human salivary glands. Water permeability was tested by regulated volume decrease (RVD) assay in BMP6 treated HSG cells with or without LDNs treatment, followed by observation of change of phospho-SMAD (pSMAD) expression as detected by Western blotting and immunofluorescent staining. In vivo activity of the ALK inhibitors was tested in C57BL/6.NOD-Aec1Aec2 mice, which have been shown to have decreased salivary gland function, by daily IP injection for 24 days and subsequent assessment of salivary gland flow rates. At the end of the study, local and systemic immune response was investigated by flow cytometric assay. In addition, the levels of pSMAD and aquaporin-5 (AQP-5) expression in submandibular glands from LDN treated mice were measured.
Conclusion: BMP6 expression is increased in a majority of pSS patients. Treatment with BMP6 inhibitors can reverse the loss of function within the salivary gland as well as decrease inflammation. These findings suggest that inhibition of BMP6 is a promising approach to the treatment of primary Sjögren’s syndrome.
To cite this abstract in AMA style:Yin H, Kalra L, Karim A, Lai Z, Guimaro M, Aber L, Swaim B, Afione S, Voigt A, Nguyen C, Yu P, Bloch D, Chiorini JA. Bone Morphogenetic Protein 6 Receptor Inhibition Restores Salivary Gland Function in a Mouse Model of Primary Sjögren’s Syndrome [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/bone-morphogenetic-protein-6-receptor-inhibition-restores-salivary-gland-function-in-a-mouse-model-of-primary-sjogrens-syndrome/. Accessed June 6, 2020.
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