The effect of conditional macrophage depletion on development of injury-induced knee OA in obese transgenic MAFIA mice

Wu, Chia‐Lung; McNeill, Jenna; Goon, Kelsey; Little, Dianne; Kimmerling, Kelly A.; Huebner, Janet L.; Kraus, V.B.; Guilak, Farshid

doi:10.1016/j.joca.2015.02.522

Cited by 2 publications

(3 citation statements)

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“…Therefore, recent studies on OA treatment have focused on alleviating inflammation using macrophage depletion. 6,28 Unfortunately, treatment based on macrophage depletion induced systemic inflammation and increased the amounts of proinflammatory cytokines in the synovial fluid and serum rather than significantly alleviating OA progression. 6 Therefore, in situ repolarization of the tissue-resident macrophage phenotype from M1 to M2 may be an effective approach for OA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…5 Conditional macrophage deletion did not attenuate OA severity and caused systemic inflammation. 6 Recent studies demonstrated that reprogramming of M1 to M2 macrophages was possible in OA treatment. 7 Several approaches, including pharmacological interventions, gene therapy, and cell-based therapy, modulate macrophage polarization during OA treatment.…”

Section: Introductionmentioning

confidence: 99%

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M2 Macrophage-Derived Extracellular Vesicles Encapsulated in Hyaluronic Acid Alleviate Osteoarthritis by Modulating Macrophage Polarization

Yuan,

Yang,

Zheng

et al. 2024

ACS Biomater. Sci. Eng.

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An imbalance between M1 and M2 macrophage polarization is critical in osteoarthritis (OA) development. We investigated the effect of M2 macrophage-derived extracellular vesicles (M2-EVs) to reprogramme macrophages from the M1 to M2 phenotype for OA treatment. M1 macrophages and mouse OA models were treated with M2-EVs. Proteomic analysis was performed to evaluate macrophage polarization in vitro. The OA models were as follows: destabilization of the medial meniscus (DMM) surgery-induced OA and collagenase-induced OA (CIOA). Hyaluronic acid (HA) was used to deliver M2-EVs. M2-EVs decreased macrophage accumulation, repolarized macrophages from the M1 to M2 phenotype, mitigated synovitis, reduced cartilage degradation, alleviated subchondral bone damage, and improved gait abnormalities in the CIOA and DMM models. Moreover, HA increased the retention time of M2-EVs and enhanced the efficiency of M2-EVs in OA treatment. Furthermore, proteomic analysis demonstrated that M2-EVs exhibited a macrophage reprogramming ability similar to IL-4, and the pathways might be the NOD-like receptor (NLR), TNF, NF-κB, and Toll-like receptor (TLR) signaling pathways. M2-EVs reprogrammed macrophages from the M1 to M2 phenotype, which resulted in beneficial effects on cartilage and attenuation of OA severity. In summary, our study indicated that M2-EV-guided reprogramming of macrophages is a promising treatment strategy for OA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

M2 Macrophage-Derived Extracellular Vesicles Encapsulated in Hyaluronic Acid Alleviate Osteoarthritis by Modulating Macrophage Polarization

Yuan,

Yang,

Zheng

et al. 2024

ACS Biomater. Sci. Eng.

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“…Beyond cartilage damage, synovial macrophage depletion caused worse synovial vascularization, fibrosis, and perivascular edema at 12 weeks post-OA induction, which was not seen with STAT1i or STAT6i. Other studies have found that transient and/or prophylactic depletion of macrophages resulted in worse synovitis, joint damage, and infiltration of T lymphocytes (31,32). In those studies, depletion was performed at a single timepoint, whereas we used repeat dosing every 2 weeks to sustain macrophage depletion/suppression.…”

Section: Discussionmentioning

confidence: 99%

Synovial macrophage activation mediates pain experiences in experimental knee osteoarthritis

Blackler

Lai-Zhao

Klapak

et al. 2023

Preprint

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It has been suggested that synovial macrophages mediate nociceptive signals in knee osteoarthritis (OA) but the underlying mechanisms are unknown. Our objectives were to investigate the role of synovial macrophages and their activation via signal transducer and activator of transcription (STAT) signaling in mediating OA pain experiences. We induced experimental OA in rats via knee destabilization surgery and then performed RNA sequencing analysis in sorted synovial macrophages to identify signaling pathways associated with macrophage activation. Next, we repeated intra-articular injections of liposomal clodronate to deplete macrophages, or liposomal inhibitors of STAT1 or STAT6 to block macrophage activation, and tested the effects on local and distal mechanical pain sensitivity. We also assessed synovitis, cartilage damage, and synovial macrophage infiltration with histopathology and immunofluorescence, and crosstalk between liposomal drug-treated synovium and articular chondrocytes in co-culture. Most enriched signaling pathways in activated OA macrophages involved STAT signalling. Macrophage depletion and STAT6 inhibition led to marked, sustained improvements in mechanical pain sensitivity and synovial inflammation compared to controls, but macrophage depletion caused increased synovial fibrosis and vascularization. In contrast, STAT1 and STAT6 inhibition in macrophages did not worsen synovial or cartilage pathology. In crosstalk assays, macrophage STAT1-inhibited synovium caused the greatest increases in the expression of anabolic and catabolic chondrocyte genes and sulphated glycosaminoglycan secretion in chondrocytes. Our results suggest that synovial macrophages play a key role in mediating pain experiences in experimental knee OA, and that selectively blocking STAT6 in synovial macrophages may reduce OA-related pain without accelerating joint tissue damage.

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The effect of conditional macrophage depletion on development of injury-induced knee OA in obese transgenic MAFIA mice

Cited by 2 publications

References 0 publications

M2 Macrophage-Derived Extracellular Vesicles Encapsulated in Hyaluronic Acid Alleviate Osteoarthritis by Modulating Macrophage Polarization

M2 Macrophage-Derived Extracellular Vesicles Encapsulated in Hyaluronic Acid Alleviate Osteoarthritis by Modulating Macrophage Polarization

Synovial macrophage activation mediates pain experiences in experimental knee osteoarthritis

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