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ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells.
Bone. 2018 04; 109:201-209.BONE

Abstract

Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Importantly, Evolutionarily Conserved Signaling Intermediate in the Toll Pathway (ECSIT) integrates TLR injury signaling with dysregulated BMP pathway signaling in FOP CTPCs. These findings provide novel insight into the cell autonomous integration of injury signals from the innate immune system with dysregulated response signals from the BMP signaling pathway and provide new exploratory targets for therapeutic approaches to blocking the induction and amplification of FOP lesions.

Authors+Show Affiliations

Department of Physiology and Biomedical Research, The Mayo Clinic, Rochester, MN, United States.Department of Pediatrics, Division of Rheumatology, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States.Department of Medicine, The Mayo Clinic, Rochester, MN, United States. Electronic address: pignolo.robert@mayo.edu.Department of Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States; Department of Medicine, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, United States. Electronic address: frederick.kaplan@uphs.upenn.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29288875

Citation

Wang, Haitao, et al. "ECSIT Links TLR and BMP Signaling in FOP Connective Tissue Progenitor Cells." Bone, vol. 109, 2018, pp. 201-209.
Wang H, Behrens EM, Pignolo RJ, et al. ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells. Bone. 2018;109:201-209.
Wang, H., Behrens, E. M., Pignolo, R. J., & Kaplan, F. S. (2018). ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells. Bone, 109, 201-209. https://doi.org/10.1016/j.bone.2017.12.024
Wang H, et al. ECSIT Links TLR and BMP Signaling in FOP Connective Tissue Progenitor Cells. Bone. 2018;109:201-209. PubMed PMID: 29288875.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells. AU - Wang,Haitao, AU - Behrens,Edward M, AU - Pignolo,Robert J, AU - Kaplan,Frederick S, Y1 - 2017/12/27/ PY - 2017/12/14/received PY - 2017/12/26/accepted PY - 2017/12/31/pubmed PY - 2018/11/20/medline PY - 2017/12/31/entrez KW - ACVR1 KW - Activin A KW - Bone morphogenetic protein (BMP) KW - Bone morphogenetic protein signaling KW - ECSIT KW - Fibrodysplasia ossificans progressiva (FOP) KW - Heterotopic ossification KW - Innate immune system KW - Toll-like receptor (TLR) SP - 201 EP - 209 JF - Bone JO - Bone VL - 109 N2 - Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Importantly, Evolutionarily Conserved Signaling Intermediate in the Toll Pathway (ECSIT) integrates TLR injury signaling with dysregulated BMP pathway signaling in FOP CTPCs. These findings provide novel insight into the cell autonomous integration of injury signals from the innate immune system with dysregulated response signals from the BMP signaling pathway and provide new exploratory targets for therapeutic approaches to blocking the induction and amplification of FOP lesions. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/29288875/ECSIT_links_TLR_and_BMP_signaling_in_FOP_connective_tissue_progenitor_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(17)30484-2 DB - PRIME DP - Unbound Medicine ER -