The exosome-like vesicles from osteoarthritic chondrocyte enhanced mature IL-1β production of macrophages and aggravated synovitis in osteoarthritis

Abstract

Synovitis, a common clinical symptom for osteoarthritis (OA) patients, is highly related to OA pathological progression and pain manifestation. The activated synovial macrophages have been demonstrated to play an important role in synovitis, but the mechanisms about macrophage activation are still not clear. In this study, we found that the exosome-like vesicles from osteoarthritic chondrocytes could be a new biological factor to stimulate inflammasome activation and increase mature IL-1β production in macrophages. The degraded cartilage explants produced more exosome-like vesicles than the nondegraded ones, while the exosome-like vesicles from chondrocytes could enter into joint synovium tissue and macrophages. Moreover, the exosome-like vesicles from osteoarthritic chondrocytes enhanced the production of mature IL-1β in macrophages. These vesicles could inhibit ATG4B expression via miR-449a-5p, leading to inhibition of autophagy in LPS-primed macrophages. The decreased autophagy promoted the production of mitoROS, which further enhanced the inflammasome activation and subsequent IL-1β processing. Ultimately, the increase of mature IL-1β may aggravate synovial inflammation and promote the progression of OA disease. Our study provides a new perspective to understand the activation of synovial macrophages and synovitis in OA patients, which may be beneficial for therapeutic intervention in synovitis-related OA patients.

Identification of microRNA‑363‑3p as an essential regulator of chondrocyte apoptosis in osteoarthritis by targeting NRF1 through the p53‑signaling pathway

“…Then, the chondrocytes were cultured in a humidified atmosphere of 37˚C and 5% CO 2 in 5 ml dMeM (invitrogen; Thermo Fisher Scientific, inc.) supplemented with 10% FBS (Gibco; Thermo Fisher Scientific, Inc.) and 1% penicillin-streptomycin. lPS-stimulation of chondrocytes is an established cellular model for the study of oa (21,22). in the present study, when the cells reached 2x10 5 /well, chondrocyte apoptosis was induced by treatment with lPS (Sigma-aldrich; Merck KGaA) at a final concentration 5 µg/ml for 6 h (18).…”

Exosomes: roles and therapeutic potential in osteoarthritis

“…Nevertheless, an increasing number of studies have revealed that both ACVs and chondrocyte-derived exosomes could mediate cell-cell communication. [105][106][107][108][109] Exosomes from primary chondrocytes cultured in a normal environment (D0 exosomes) could restore mitochondrial dysfunction and enhance M2 macrophage penetration with a reduction in M1 macrophages. 106 The intra-articular administration of D0 exosomes efficiently delayed OA progression.…”

“…106 We found that exosome-like vesicles derived from osteoarthritic chondrocytes could stimulate inflammasome activation and increase mature IL-1β production in macrophages via the miR-449a-5p/ATG4B/autophagy pathway, which may aggravate synovitis and accelerate the progression of OA. 107 In addition, Chen et al reported that exosomes derived from chondrocytes (CC-Exos) could induce efficient ectopic chondrogenesis of cartilage progenitor cell (CPC) constructs in subcutaneous environments, which may represent a cell-free therapeutic approach for cartilage regeneration. 108 Moreover, chondrocyte-secreted exosomes could affect chondrogenic differentiation and cartilage matrix synthesis via the miR-95-5pregulated expression of HDAC2/8.…”

“…The exosomes from osteoarthritic chondrocytes (OC-Exos) could stimulate IL-1beta processing and production in macrophages via miR-449a-5p-mediated autophagy inhibition. 107 miR-449a-5p can bind to the 3′-UTR of the ATG4B gene to inhibit its expression, which leads to autophagy inhibition and inflammasome activation of macrophages in vitro and may ultimately promote synovitis and cartilage erosion in DMMinduced mice. 107 Antagonizing miR-449a-5p reversed OC-Exomediated proinflammatory effects and cartilage destruction, which provided a new perspective for OA treatment based on miR-449a-5p of OC-Exos.…”

Exosomes in osteoarthritis and cartilage injury: advanced development and potential therapeutic strategies

“…In one chip-assay study, 50 miRNAs were identified in exosomes in response to IL-1βstimulated SFB compared to in non-stimulated SFB, and among them, miR-4454 and miR-199b are related to inflammatory stimulation [18] and cartilage formation [19] , respectively. Ni et al found the exosome-like vesicles from IL-1β-pretreated chondrocytes could promote mature IL-1β production of macrophages [20] .…”