Inflammation in Fibrodysplasia Ossificans Progressiva and Other Forms of Heterotopic Ossification.

PURPOSE OF REVIEW: Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO. RECENT FINDINGS: Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.

Tissue-engineered blood vessel mimics in complex geometries for intravascular device testing.

OBJECTIVE: Intravascular stents are commonly used to treat occluded arteries during coronary heart disease. After coronary stent implantation, endothelial cells grow over the stent, which is referred to as re-endothelialization. Re-endothelialization prevents blood from clotting on the stent surface and is a good predictor of stent success. Blood vessel mimics (BVMs) are in vitro tissue-engineered models of human blood vessels that may be used to preclinically test stents for re-endothelialization. BVMs have been developed in straight geometries. However, the United States Food and Drug Administration recommends that devices intended to treat coronary occlusions be preclinically tested in bent and bifurcated vessels due to the complex geometries of native coronary arteries. The main objectives of this study were to develop and characterize BVMs in complex geometries. DESIGN: Bioreactors were designed and constructed so that BVMs could be cultivated in bent (>45°) and bifurcated geometries. Human umbilical vein endothelial cells were sodded onto complex-shaped scaffolds, and the resulting BVMs were characterized for cell deposition. For a final proof of concept, a coronary stent was deployed in a severely angulated BVM. RESULTS: The new bioreactors were easy to use and mounting scaffolds in complex geometries in the bioreactors was successful. After sodding scaffolds with cells, there were no statistically significant differences between the cell densities along the length of the BVMs, on the top and bottom halves of the BVMs, or on the inner and outer halves of the BVMs. This suggests cells deposited evenly throughout the scaffolds, resulting in consistent complex-geometry BVMs. Also, a coronary stent was successfully deployed in a severely angulated BVM. CONCLUSIONS: Bioreactors can be constructed for housing complex-shaped vessels. BVMs can be developed in the complex geometries observed in native coronary arteries with endothelial cells evenly dispersed throughout BVM lumens.

Prg4 prevents osteoarthritis induced by dominant-negative interference of TGF-ß signaling in mice.

OBJECTIVE: Prg4, also known as Lubricin, acts as a joint/boundary lubricant. Prg4 has been used to prevent surgically induced osteoarthritis (OA) in mice. Surgically induced OA serves as a good model for post-traumatic OA but is not ideal for recapitulating age-related OA. Reduced expression of the TGF-ß type II receptor (TGFßR2) is associated with age-related OA in clinical samples, so we previously characterized a mouse model that exhibits OA due to expression of a mutated dominant-negative form of TGFßR2 (DNIIR). Prg4 expression was significantly reduced in DNIIR mice. Furthermore, we showed that Prg4 was a transcriptional target of TGF-ß via activation of Smad3, the main signal transducing protein for TGF-ß. The objective of the present study was to determine whether maintenance of Prg4, a down-stream transcriptional target of TGF-ß, prevents OA associated with attenuated TGF-ß signaling in mice. DESIGN: Wild-type, DNIIR, and bitransgenic mice that express both DNIIR and Prg4, were compared. Mice were assessed with a foot misplacement behavioral test, µCT, histology, and Western blot. RESULTS: Compared to DNIIR mice, bitransgenic DNIIR+Prg4 mice missed 1.3 (0.4, 2.1) fewer steps while walking (mean difference (95% confidence interval)), exhibited a cartilage fibrillation score that was 1.8 (0.4, 3.1) points lower, exhibited cartilage that was 28.2 (0.5, 55.9) µm thicker, and exhibited an OARSI score that was 6.8 (-0.9, 14.5) points lower. However, maintenance of Prg4 expression did not restore levels of phosphorylated Smad3 in DNIIR mice, indicating Prg4 does not simply stimulate TGF-ß signaling. CONCLUSIONS: Our results indicate that maintenance of Prg4 expression prevents OA progression associated with reduced TGF-ß signaling in mice. Since there was no evidence that Prg4 acts by stimulating the TGF-ß signaling cascade, we propose that Prg4, a transcriptional target of TGF-ß, attenuates OA progression through its joint lubrication function.