Inflammation in Osteoarthritis an M1/M2 imbalance. M1/M2 target for diag and treat-NL | NAVB Message Board Posts


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Msg  40538 of 40762  at  11/28/2023 3:19:21 PM  by

moneyonomics


Inflammation in Osteoarthritis an M1/M2 imbalance. M1/M2 target for diag and treat-NL

Continuing studies point to growing growing validation inflammation in Osteoarthritis is an M1/M2 imbalance so M1/M2 should be a target for diagnosis and treatment
 
 
Published online 2023 Mar 24. doi: 10.3390/ijms24076112
PMCID: PMC10094694
PMID: 37047082

Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development

Rodolfo Gõmez, Academic Editor

Abstract

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies...

 

...In addition, it is hypothesized that during the progression of OA, macrophage phenotype in the joint itself is switched, initiating a feedforward loop with continual release of pro-inflammatory factors, triggering chronic inflammation in attempts to repair the damaged tissue [,]. Bailey et al. (2020) noted a shift in macrophage M1/M2 ratio following joint damage in mice, leading to the dominance of M1-like macrophages and a reduction of M2-like macrophages in the synovium []. In particular, pro-inflammatory macrophage polarization is associated with triggering other tissue responses seen in OA, such as synovial inflammation. Synovitis is observed in the early stages of OA [,], and it has been reported to precede the development of radiographic knee osteoarthritis [,]. For instance, patients with early OA have greater macrophage cell infiltration, blood vessel formation, and a significantly higher number of cells producing inflammatory cytokines such as TNF and IL-1β when compared to patients with late OA []. Nevertheless, on magnetic resonance imaging (MRI), synovitis is also observed in the later stages of OA []. Synovitis seems to contribute towards OA progression, with a higher synovitis score corresponding to an increased risk of OA incidence, an increase in chronic pain, and joint inflammation [,]. When investigating the ratio of M1-like and M2-like macrophages in OA knees and healthy control knees, synovial fluid macrophages and peripheral blood monocytes showed higher M1-like versus M2-like markers in patients with OA compared to healthy controls []. Flow cytometry and RT-qPCR showed a significantly higher expression of the CD11c marker (M1) in the synovial fluid of knees with OA compared to CD206 expression (M2), and the ratio of M1 and M2 macrophages was positively correlated with the level of the Kellgren-Lawrence grade in knee OA, implying high OA severity [].

Macrophage activity in OA has led to studies investigating whether cartilage and joint health benefit from macrophage modulation []. Studies on therapeutic applications have focused on developing alternative designs to inhibit pro-inflammatory signal transduction carried out by the innate immune system [,]. Building upon previously established knowledge of TGF-β in inducing osteophyte formation in murine joints, macrophages were identified to be crucial intermediaries in TGF-β induced osteophytes and chondrogenesis [,]. Depletion of synovium macrophages in normal murine knee joints via injection of clodronate-laden liposomes resulted in significantly decreased osteophyte formation (by 70%) despite TGF-β stimulation []. In addition, supplementation of corticosteroids, such as dexamethasone, to synovial explants of patients with knee OA resulted in a decrease of pro-inflammatory M1-like macrophages and enhancement of anti-inflammatory M2-like macrophages []. Rabbits with OA have a decrease in cartilage degeneration, fewer infiltration of CD68+ cells, and less severe inflammation when provided with an intra-articular injection of mevastatin, which arrests monocyte differentiation []. These studies indicate that monocyte and macrophage-targeted strategies could be beneficial in OA treatment. However, timing, dosage, and delivery (locally versus systemically) are important factors to consider when applying macrophage depletion strategies, as the normal, non-chronic macrophage response is essential in tissue healing [,]. Moreover, monocyte depletion does not always yield a positive result for joint health, as when macrophages and monocytes are depleted systemically prior to knee joint medial collateral ligament rupture in a rat model, impaired healing and ligament strength are observed [], and hence it should be taken into consideration. Similarly, when macrophages are depleted systemically in an obese mouse OA model, inflammation is reported to increase with infiltration of neutrophils and T cells in the joint synovium, and these mice developed OA following destabilization of the medial meniscus (DMM) surgery, demonstrating the importance of macrophages in joint homeostasis [].

3. Macrophages and the Metabolic OA Phenotype

As mentioned, obesity and obesity-associated MetS are known to be key risk factors for the development and progression of OA [,]. Initial research into the pathophysiology of obesity-related OA highlighted a mechanical element, such as increased loading on weight-bearing joints in driving structural damage [,]. However, obesity has also been shown to increase the risk of OA in non-weight-bearing joints, such as the hands [,,]. These various studies set forth strong evidence for a systemic influence in obesity-related OA, as mechanical stress does not explain the prevalence of OA in non-weight-bearing joints. This prompted research into adipose tissue and metabolic factors in the development of OA, and the identification of a new OA subtype, the MetS-OA phenotype []....

 
 

...5. Conclusions

In summary, OA is far from being defined exclusively as a wear-and-tear disease, as inflammatory processes have also been shown to be implicated in the development and progression of OA. The metabolic OA phenotype comprises a substantial group of OA patients, which have in common that they present low-grade systemic inflammation as a result of metabolic disturbances. An imbalance between macrophage M1- and M2-like phenotypes are thought to be a part of the underlying mechanism of this chronic condition. Pro-inflammatory signaling drives macrophage polarization towards the M1-like phenotype, resulting in a prolonged state of inflammation, synovitis, cartilage damage, and osteophyte formation, as seen in OA. Research on macrophage-related biomarkers in OA shows potential in terms of use in early diagnostics and monitoring of disease progression. Studies have identified biomarkers such as FR-β, blood-based VICM, and other soluble biomarkers indicative of increased macrophage activation, opening up possibilities for their use in early diagnosis, monitoring of joint tissue inflammation progress, and also in drug development trials assessing treatment response. Several pre-clinical studies have successfully applied therapeutic approaches targeting the inhibition of pro-inflammatory signals or macrophage depletion strategies. These strategies show a degree of effectiveness in managing symptoms of OA, such as osteophyte formation, synovitis, and cartilage degeneration. However, ensuring that the healthy macrophage response pertinent to tissue regulation and healing is unaltered is necessary. As knowledge of the inflammatory processes involved in OA onset and progression expands, we get closer to identifying inflammatory biomarkers that will be suitable for early diagnosis in monitoring the disease progression and/or treatment strategies. Therefore, the identification of such biomarkers will be a hallmark not only in early disease detection but will also facilitate tailoring treatment.

 


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