Replenishing decoy extracellular vesicles inhibits phenotype remodeling of tissue-resident cells in inflammation-driven arthritis.

The interleukin 6 (IL6) signaling pathway plays pleiotropic roles in regulating the inflammatory milieu that contributes to arthritis development. Here, we show that activation of IL6 trans-signaling induces phenotypic transitions in tissue-resident cells toward an inflammatory state. The establishment of arthritis increases the serum number of extracellular vesicles (EVs), while these EVs express more IL6 signal transducer (IL6ST, also known as gp130) on their surface. Transferring these EVs can block IL6 trans-signaling in vitro by acting as decoys that trap hyper IL6 and prevent inflammatory amplification in recipient arthritic mice. By genetically fusing EV-sorting domains with extracellular domains of receptors, we engineered EVs that harbor a higher quantity of signaling-incompetent decoy receptors. These exogenous decoy EVs exhibit significant potential in eliciting efficient anti-inflammatory effects in vivo. Our findings suggest an inherent resistance of decoy EVs against inflammation, highlighting the therapeutic potential of efficient decoy EVs in treating inflammatory diseases.

Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling.

Bone remodeling is precisely coordinated by bone resorption and formation. Apoptotic osteoclasts generate large amounts of apoptotic bodies (ABs) marking the end of the bone resorption phase, whereas the functions of osteoclast-derived ABs remain largely unknown. Here, we identified the molecular profile of ABs derived from osteoclasts at distinct differentiation stages and investigated their corresponding functions. ABs were isolated from apoptotic bone marrow macrophages, preosteoclasts, and mature osteoclasts induced by staurosporine. Proteomic signature analysis with liquid chromatography-tandem mass spectrometry suggested marked protein cargo differences among the different ABs. Further bioinformatic analysis showed that the proteomic signatures of the ABs were highly similar to those of their parental cells. Functionally, pOC-ABs induced endothelial progenitor cell differentiation and increased CD31hiEmcnhi endothelial cell formation in a murine bone defect model via their PDGF-BB cargo. mOC-ABs induced osteogenic differentiation of mesenchymal stem cells and facilitated osteogenesis via RANKL reverse signaling. In summary, we mapped the detailed proteomic landscapes of ABs derived from osteoclasts and showed that their potential biological roles are important in coupling bone formation with resorption during bone remodeling.

The role of physical forces in osteoclastogenesis.

The movements of life at every level from organs, tissues, cells to sub-cells, are all conducted in certain physical environments. In the human body, skeletal tissue among all connective tissues is influenced the most by physical forces. Studying the biological behavior of bone cells under different physical environments is helpful in further understanding bone homeostasis and metabolism. Among all bone cells, osteoclast (OC) and OC steered bone remodeling is one of the key points in bone metabolism. In the past few decades, people's understanding of OC was mostly limited to its involvement of bone resorption under physiological and pathological conditions. However, more and more studies started to focus on how physical forces affect the formation and differentiation of OC. This review tries to illustrate the knowledge up to date about how osteoclastogenesis is regulated by physical forces through direct and indirect ways, including fluid shear force, compressive force, and microgravity. The direct way describes the straightforward effects produced by different forces in osteoclastogenesis, whereas the indirect way describes the effects of different forces in osteoclastogenesis through regulation of other bone cells when a certain force is applied. Molecular mechanisms were analyzed and reviewed in both direct and indirect regulation by different forces. Finally, we discussed the status quo and tendency of related research, as well as other unresolved issues, and some future prospects.