Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis.
Lavinia RaimondiAngela De LucaSimona FontanaNicola AmodioViviana CostaValeria CarinaDaniele BellaviaStefania RaimondoSergio SiragusaFrancesca MonteleoneRiccardo AlessandroMilena FiniGianluca GiavaresiPublished in: Cancers (2020)
Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1α/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1α by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1α (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption.
Keyphrases
- endoplasmic reticulum
- transcription factor
- endoplasmic reticulum stress
- multiple myeloma
- end stage renal disease
- bone loss
- newly diagnosed
- type diabetes
- prognostic factors
- chronic pain
- induced apoptosis
- chronic kidney disease
- bone mineral density
- machine learning
- minimally invasive
- inflammatory response
- spinal cord injury
- oxidative stress
- risk factors
- cardiovascular events
- small molecule
- big data
- adipose tissue
- pi k akt
- patient reported
- coronary artery disease
- neuropathic pain
- artificial intelligence
- induced pluripotent stem cells
- patient reported outcomes
- atomic force microscopy