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.
Subject(s)
Activin Receptors, Type I/antagonists & inhibitors , Bone Morphogenetic Protein 6/metabolism , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Quinolines/administration & dosage , Salivary Glands/pathology , Sjogren's Syndrome/drug therapy , Activin Receptors, Type I/metabolism , Adult , Aged , Animals , Bone Morphogenetic Protein 6/analysis , Bone Morphogenetic Protein 6/genetics , Cell Line , Female , Healthy Volunteers , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Phosphorylation/drug effects , Recovery of Function/drug effects , Saliva/immunology , Saliva/metabolism , Salivary Glands/drug effects , Salivary Glands/metabolism , Salivary Glands/physiopathology , Signal Transduction/drug effects , Sjogren's Syndrome/immunology , Sjogren's Syndrome/pathology , Sjogren's Syndrome/physiopathology , Smad Proteins, Receptor-Regulated/metabolism , Young AdultABSTRACT
A murine distraction osteogenesis model was standardized to allow analysis of the molecular pathways associated with postnatal de novo bone formation. The authors examined the presence and expression of Bone Morphogenetic Proteins (BMPs) -2, -3, -4, -6 and -7, and the BMP receptors Alk3 and Alk6 at different stages. Strong signals were detected for BMP-4 at the end of the distraction period and for BMP-6 during the entire experimental period. Signals for BMP-7 (Osteogenic Protein-1) were very low, suggesting a less important role during the normal process of distraction bone healing. Immunohistochemical staining revealed the presence of BMP-4 in the early chondroblasts, while BMP-6 was detected in the more mature cartilage cells. The data indicate a BMP molecular profile reminiscent of the embryonic maturation process in endochondral bone formation.
