Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by a Camouflaged Meta‐Defensome

Zhang, Lei; Chen, Xiang; Cai, Pingqiang; Sun, Han; Shen, Siyu; Guo, Bin; Jiang, Qing

doi:10.1002/adma.202202715

Cited by 45 publications

(41 citation statements)

References 130 publications

(53 reference statements)

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“…In addition, various nitric oxide (NO) scavengers and iNOS inhibitors have exhibited strong anti‐inflammatory and macrophage reprogramming effects by suppressing intracellular and extracellular concentrations of NO because NO produced by M1 macrophages is 30‐fold higher than that produced by M2 macrophages. [ 11 ] However, their use is limited to rheumatoid arthritis and early‐stage OA treatment. Therefore, we hypothesized that a two‐pronged scavenging strategy based on CA9 and NO might improve progressive OA by inhibiting intracellular and extracellular concentrations of NO and H + to promote the reprogramming of synovial macrophages.…”

Section: Introductionmentioning

confidence: 99%

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis

Yan

Dou

et al. 2023

Advanced Science

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Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two‐pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in “two‐in‐one” nanocarriers (NAHA‐CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro‐chondrogenic TGF‐β1 mRNA (≈1.3‐fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti‐inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid‐induced early and late OA mouse models and a surgical destabilization of medial meniscus‐induced OA rat model. Therefore, the siCA9 and NO scavenger “two‐in‐one” delivery system is a potential and efficient strategy for progressive OA treatment.

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Section: Introductionmentioning

confidence: 99%

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis

Yan

Dou

et al. 2023

Advanced Science

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“…As mitochondria are vital subcellular organelles producing ROS and energy, it is universally acknowledged that the balance of mitochondrial dynamics is essential for cellular metabolism and critically associated with the physiological status. [31,34] Current views on the mechanism of anti-inflammatory and antioxidant effects of TDN-based nanomaterials refer to their ability to scavenge ROS. [13,14,35] Therefore, it is hypothesized that DNA nanostructures might enter the cell cytoplasm and reach mitochondria at a certain extent.…”

Section: Mitochondrial Dynamicsmentioning

confidence: 99%

Functionalized DNA Nanomaterials Targeting Toll‐Like Receptor 4 Prevent Bisphosphonate‐Related Osteonecrosis of the Jaw via Regulating Mitochondrial Homeostasis in Macrophages

Zhang

et al. 2023

Adv Funct Materials

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Imbalance of macrophage polarization characterized by an increase in the percentage of pro-inflammatory M1 macrophages and a decrease in anti-inflammatory M2 macrophages is considered a critical pathogenic mechanism of bisphosphonate-related osteonecrosis of the jaws (BRONJ).Because high levels of Toll-like receptor 4 (TLR4) mediates mitochondrial dyshomeostasis in Zoledronic Acid (ZA)-treated M1 macrophages, tetrahedral DNA nanomaterial (TDN)-modified with TLR4-siRNA on each vertex (TDN-TLR4-4siR) with excellent biocompatibility is synthesized. This novel TDN-TLR4-4siR nanomaterial reverses the polarization phenotype imbalance decreasing the percentage of M1 RAW264.7 macrophages. Mitochondrial dynamics analysis shows a shift from short rod-like ultrastructure to elongated shapes with more mitochondrial network continuity in ZA-primed M1 macrophages after treatment with TDN-TLR4-4siR, along with elevated expression of Mfn1 and Mfn2. TDN-TLR4-4siR further reduces intracellular ROS production and restored mitochondrial membrane potential. Furthermore, decreased sequestra formation and accelerated healing of the extraction wound are observed in the TDN-TLR4-4siR group, resulting in decreased incidence of rat BRONJ via reprogramming polarized macrophages. Consequently, this study establishes a novel strategy using TDN-TLR4-4siR nanomaterial to regulate mitochondrial homeostasis of polarized macrophages to prevent BRONJ.

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“…[8] Similarly, Zhang et al prepared a camouflaged meta-defensome to transform M1 synovial macrophages into the M2 phenotype, allowing mitochondrial metabolic reprogramming for antagonizing OA. [9] However, the specific mechanisms by which mitochondria affect OA as well as the pivotal regulators involved are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

et al. 2023

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Mitochondrial homeostasis is of great importance for cartilage integrity and associated with the progression of osteoarthritis (OA); however, the underlying mechanisms are unknown. This study aims to investigate the role of mitochondrial deacetylation reaction and investigate the mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation with the severity of OA in both human arthritic cartilage and mice inflammatory chondrocytes. Global SIRT3 deletion accelerates pathological phenotype in post‐traumatic OA mice, as evidenced by cartilage extracellular matrix collapse, osteophyte formation, and synovial macrophage M1 polarization. Mechanistically, SIRT3 prevents OA progression by targeting and deacetylating cytochrome c oxidase subunit 4 isoform 2 (COX4I2) to maintain mitochondrial homeostasis at the post‐translational level. The activation of SIRT3 by honokiol restores cartilage metabolic equilibrium and protects mice from the development of post‐traumatic OA. Collectively, the loss of mitochondrial SIRT3 is essential for the development of OA, whereas SIRT3‐mediated proteins deacetylation of COX4I2 rescues OA‐impaired mitochondrial respiratory chain functions to improve the OA phenotype. Herein, the induction of SIRT3 provides a novel therapeutic candidate for OA treatment.

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Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by a Camouflaged Meta‐Defensome

Cited by 45 publications

References 130 publications

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis

Functionalized DNA Nanomaterials Targeting Toll‐Like Receptor 4 Prevent Bisphosphonate‐Related Osteonecrosis of the Jaw via Regulating Mitochondrial Homeostasis in Macrophages

Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

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