MiR-92a/KLF4/p110δ regulates titanium particles-induced macrophages inflammation and osteolysis

Abstract

As total joint replacement is widely applied for severe arthropathy, peri-prosthetic aseptic loosening as one of the main causes of implant failure has drawn wide attention. Wear particles such as titanium particles (TiPs) derived from prosthesis can initiate macrophages inflammation and sequentially activate osteoclasts, which results in bone resorption and osteolysis for long-term. Therefore, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL. In this research, we found that the inhibition of p110δ, a member of class IA PI3Ks family, could significantly dampen the TiPs-induced secretion of TNFα and IL-6. By the transfection of siRNA targeting p110δ, we confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. As the upstream transcription-repressor of p110δ, Krüppel-like factor 4 (KLF4), targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. To further ascertain the roles of KLF4/p110δ, TiPs-induced mice cranial osteolysis model was established and vivo experiments validated that KLF4-knockdown could exacerbate TiPs-induced osteolysis, which was strikingly ameliorated by knockdown of p110δ. In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis.

NOD2 attenuates osteoarthritis via reprogramming the activation of synovial macrophages

“…Synovial inflammation is detected throughout the entire process of OA development [ 22 ], preceding other pathological changes of OA, as a predictive marker before the onset of OA. Macrophages are profoundly involved in various diseases including developmental, inflammatory, tumoral, and degenerative diseases [ 23 , 24 ]. Direct in vivo evidence of macrophage involvement in human osteoarthritis has been validated, by revealing the fact that activated, not resting macrophages, were recruited in 76% of OA knees [ 24 ].…”

“…Macrophages are profoundly involved in various diseases including developmental, inflammatory, tumoral, and degenerative diseases [ 23 , 24 ]. Direct in vivo evidence of macrophage involvement in human osteoarthritis has been validated, by revealing the fact that activated, not resting macrophages, were recruited in 76% of OA knees [ 24 ]. Therefore, understanding the regulatory mechanism of macrophage activation is crucial in OA pathogenesis.…”

Inhibition of miR-25 Ameliorates Cardiac Dysfunction and Fibrosis by Restoring Krüppel-like Factor 4 Expression

“…In our study, considering the anti-inflammatory effects of KLF4 in different tissues [31][32][33], and that mononuclear cell infiltration was reduced upon miR-25 TuD delivery in our histological data, we hypothesized that miR-25 inhibition may also alleviate cardiac inflammation in the context of Ang II-induced cardiac hypertrophy. To test this hypothesis, we examined the expression of pro-inflammatory proteins, including Galectin-3 and MCP-1, in the same mouse heart tissue.…”

STING/TBK1 Regulates Inflammation in Macrophages and Titanium Particles-Induced Osteolysis

“…), which facilitate osteoclasts' bone resorption and finally result in AL. 4 Hence, studying the mechanism of wear particles-induced inflammatory response in macrophages and identifying the key molecules will provide a novel therapy strategy to prevent the development of AL and to prolong the lifespan of prostheses.…”

“…However, studies report that limited prostheses’ service life attributing to aseptic loosening (AL) greatly affects patients’ living quality and increases economic burden and finally leads to revision surgery which complicates with a higher failure risk. , Mechanistically, wear particles, released from prostheses’ surface, can activate macrophages to produce inflammatory factors (TNF-α, IL-6, etc. ), which facilitate osteoclasts’ bone resorption and finally result in AL . Hence, studying the mechanism of wear particles-induced inflammatory response in macrophages and identifying the key molecules will provide a novel therapy strategy to prevent the development of AL and to prolong the lifespan of prostheses.…”