Osteoarthritis (OA) is a chronic degenerative osteoarthropathy. Although it has been revealed that a variety of factors can cause or aggravate the symptoms of OA, the pathogenic mechanisms of OA remain unknown. Reliable OA models that accurately reflect human OA disease are crucial for studies on the pathogenic mechanism of OA and therapeutic drug evaluation. This review first demonstrated the importance of OA models by briefly introducing the OA pathological features and the current limitations in the pathogenesis and treatment of OA. Then, it mainly discusses the development of different OA models, including animal and engineered models, highlighting their advantages and disadvantages from the perspective of pathogenesis and pathology analysis. In particular, the state-of-the-art engineered models and their potential were emphasized, as they may represent the future direction in the development of OA models. Finally, the challenges in obtaining reliable OA models are also discussed, and possible future directions are outlined to shed some light on this area.
Bis(monoacylglycero)phosphate (BMP) is an unusually shaped, negatively charged phospholipid found in elevated concentrations in the late endosomes. The unusual structure and stereochemistry of BMP are thought to play important roles in the endosome, including structural integrity, endosome maturation, and lipid/protein sorting and trafficking. We have utilized dynamic light scattering, fluorescence spectroscopy and transmission electron microscopy to characterize the morphology and size of BMP hydrated dispersions and extruded vesicles. We find that the morphology of hydrated BMP dispersions varies with pH, forming highly structured, clustered dispersions of 500 nm in size at neutral pH 7.4. However, at acidic pH 4.5, spontaneous hydrolysis of BMP occurs, altering the vesicle morphology to spherically shaped dispersions. BMP vesicles are also significantly smaller in diameter than palmitoyloleoylglycerophosphocholine (POPC) vesicles. In a stability assay using dynamic light scattering measurements to compare and monitor 30 nm extruded vesicles of BMP, POPC, and POPG over a 5 week period, we find that BMP vesicles do not fuse to form larger structures. BMP also forms lamellar vesicles evidenced by the fluorescence leakage assay studies. These results shed light on the possibility that the biosynthesis of BMP and the increasing acidity during the maturation process of late endosomes play an important role in the formation of intraendosomal vesicular bodies.
Mutations in dysferlin cause Limb-Girdle and Miyoshi Muscular Dystrophy. Dysferlin is structurally related to Otoferlin, a protein involved in the calcium triggered release of neurotransmitters in cochlear hair cells. Dysferlin is a calcium-binding protein with a single membrane-spanning domain thought to be required for membrane wound repair. The specific function that dysferlin performs in wound healing is unknown. Here we report the activation of an intercellular signaling pathway in sea urchin embryos by membrane wounding that evokes calcium spikes in neighboring cells. This pathway was mimicked by ATP application, and inhibited by apyrase, cadmium, and omega-agatoxin IVA. Microinjection of dysferlin antisense morpholinos blocked this pathway; control morpholinos did not. Co-injection of mRNA encoding human dysferlin with the inhibitory morpholino rescued signaling activity. Our results indicate that membrane wounding triggers membrane depolarization, calcium influx through an agatoxin sensitive voltage-gated calcium channel, and ultimately the secretion of ATP. Moreover, dysferlin appears to mediate one of the essential steps in this signaling cascade.
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