| Autor: |
Lyu H; Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.; Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha 410000, China., Elkins CM; Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA., Pierce JL; Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA., Serezani CH; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Perrien DS; Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA. |
| Abstrakt: |
Excess inflammation and canonical BMP receptor (BMPR) signaling are coinciding hallmarks of the early stages of injury-induced endochondral heterotopic ossification (EHO), especially in the rare genetic disease fibrodysplasia ossificans progressiva (FOP). Multiple inflammatory signaling pathways can synergistically enhance BMP-induced Smad1/5/8 activity in multiple cell types, suggesting the importance of pathway crosstalk in EHO and FOP. Toll-like receptors (TLRs) and IL-1 receptors mediate many of the earliest injury-induced inflammatory signals largely via MyD88-dependent pathways. Thus, the hypothesis that MyD88-dependent signaling is required for EHO was tested in vitro and in vivo using global or Pdgfrα-conditional deletion of MyD88 in FOP mice. As expected, IL-1β or LPS synergistically increased Activin A (ActA)-induced phosphorylation of Smad 1/5 in fibroadipoprogenitors (FAPs) expressing Alk2 R206H . However, conditional deletion of MyD88 in Pdgfrα-positive cells of FOP mice did not significantly alter the amount of muscle injury-induced EHO. Even more surprisingly, injury-induced EHO was not significantly affected by global deletion of MyD88. These studies demonstrate that MyD88-dependent signaling is dispensable for injury-induced EHO in FOP mice. |
