Abstract
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 Alk2R206H. 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.
Highlights
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disease caused by one of several point mutations in the BMP type I receptor, ALK2 [1,2] and results in episodes of hyperinflammatory, fibroproliferative, and edematous soft tissue lesions, termed “flares”, that frequently progress to intramuscular endochondral heterotopic ossification (EHO) [3,4,5,6]
To determine whether Toll-like receptors (TLRs) or IL1 receptor 1 (IL1R1) signaling enhances Activin A (ActA)/Alk2R206H signaling, phosphorylation of Smad1/5 was measured in murine Alk2w/w and Alk2R206H_FlEx/w FAPs treated with ActA alone or in combination with LPS or IL-1β (Figure 1)
Resorption areas that were large enough marrow cell invasion were often filled with acellular matrix, resembling collagen deposifor marrow cell invasion were often filled with acellular matrix, resembling collagen tion (Figure 5D). While these histological observations suggest the remodeling of cartilage to bone may be impaired in MyD88−/− FOP mice, this study demonstrates that MyD88dependent signaling has a surprisingly limited, if any, role during EHO in FOP
Summary
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disease caused by one of several point mutations in the BMP type I receptor, ALK2 [1,2] and results in episodes of hyperinflammatory, fibroproliferative, and edematous soft tissue lesions, termed “flares”, that frequently progress to intramuscular endochondral heterotopic ossification (EHO) [3,4,5,6]. Heterotopic ossification (HO) is a pathological process of extraskeletal osteogenesis in muscle and soft tissue. HO progressively replaces skeletal muscles, typically leading to joint ankylosis, disfigurement, pain, and loss of mobility [3,5,7,8]. In addition to FOP, EHO is a common clinical complication of musculoskeletal trauma and other rare genetic diseases. The most common FOP-causing mutation is ACVR1617G>A , which encodes ALK2R206H [1] There are currently no approved effective treatments for FOP, and knowledge of the underlying mechanisms is very limited.
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