Effects of the Interleukin-6 Receptor Blocker Sarilumab on Metabolic Activity and Differentiation Capacity of Primary Human Osteoblasts

Klinder, Annett; Waletzko-Hellwig, Janine; Sellin, Marie-Luise; Seyfarth-Sehlke, Anika; Wolfien, Markus; Prehn, Franziska; Bader, Rainer; Jonitz‐Heincke, Anika

doi:10.3390/pharmaceutics14071390

Cited by 3 publications

(10 citation statements)

References 46 publications

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“…However, an increase in hemopexin levels, in sense, may signify some types of anemia (in particular, hemolytic anemia), as well as chronic inflammatory processes caused by the high activity of cytokines and anaphylatoxins (complement factors), and suppression of immune reactivity [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Determination of Heterogeneous Proteomic and Metabolomic Response in anti-TNF and anti-IL-6 Treatment of Patients with Rheumatoid Arthritis

Stepanov¹,

Malsagova²,

Kopylov³

et al. 2023

Life

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Reduction in tumor necrosis factor (αTNF) and interleukin-6 (IL-6) activities is a widely utilized strategy for the treatment of rheumatoid arthritis (RA) with a high success rate. Despite both schemes targeting the deprivation of inflammatory reactions caused by the excessive activity of cytokines, their mechanisms of action and the final output are still unequal. This was a comparative longitudinal study that lasted for 24 weeks and aimed to find the answer to why the two schemes of therapy can pass out of proportion in attitude of their efficiency. What are the differences in metabolic and proteomic responses among patients who were being treated by either the anti-TNF or anti-IL-6 strategy? We found increased levels of immunoglobulins A and G (more than 2-fold in anti-IL-6 and more than 4-5-fold in anti-TNF groups) at the final stage (24 weeks) of monitoring but the most profound increase was determined for µ-chains of immunoglobulins in both groups of study. Metabolomic changes displayed main alterations with regard to arginine metabolism and collagen maintenance, where arginine increased 8.86-fold (p < 0.001) in anti-TNF and 5.71-fold (p < 0.05) in anti-IL-6 groups but patients treated by the anti-TNF scheme suffered a higher depletion of arginine before the start of therapy. Some indicators of matrix and bone tissue degradation also increased 4-hydroxyproline (4-HP) more than 6-fold (p < 0.001) in anti-TNF and more than 2-fold (p < 0.05) in the anti-IL-6 group, but the growth dynamics in the anti-IL6 group was delayed (gradually raised at week 24) compared to the anti-TNF group (raised at week 12) following a smooth reduction. The ELISA analysis of IL-6 and TNFα concentration in the study population supported proteomic and metabolomic data. A positive correlation between ΔCDAI and ΔDAS28 indicators and ESR and CRP was established for the majority of patients after 24 weeks of treatment where ESR and CRP reduced by 20% and 40% finally, respectively. A regression model using the Forest Plot was estimated to elucidate the impact of the most significant clinical, biochemical, and anthropometric indicators for the evaluation of differences between considered anti-TNF and anti-IL-6 schemes of therapy.

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Section: Discussionmentioning

confidence: 99%

Determination of Heterogeneous Proteomic and Metabolomic Response in anti-TNF and anti-IL-6 Treatment of Patients with Rheumatoid Arthritis

Stepanov¹,

Malsagova²,

Kopylov³

et al. 2023

Life

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“…IL-6 can interact with cells only in the presence of soluble IL-6R, so IL-6 was used in combination with sIL-6R for treatment. The influence of different concentrations of the cytokine and its receptor on the cells was investigated in a previous study [ 11 ]. In this study, it was shown that only high concentrations of 50 ng/mL each for IL-6 and sIL-6R caused an effect; therefore, these concentrations were used in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the dosing regimen (200 mg every two weeks for human application) that was associated with a significant improvement of the symptoms in RA patients, the sarilumab concentration of 250 nM (40 µg/ml, Kevzara®, Sanofi-Aventis, Montpellier, France) was considered for cell culture experiments. All concentrations were based on our previous study [ 11 ]. If not otherwise stated, the following stimulation groups were defined: (i) sarilumab, (ii) IL-6 + sIL-6R, (iii) IL-6 + sIL-6R + sarilumab, and iv) unstimulated control.…”

Section: Methodsmentioning

confidence: 99%

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IL-6-induced response of human osteoblasts from patients with rheumatoid arthritis after inhibition of the signaling pathway

Sellin¹,

Klinder²,

Bergschmidt³

et al. 2023

Clin Exp Med

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Interleukin (IL-) 6 is a critical factor in inflammatory processes of rheumatoid arthritis (RA). This is of high interest as the progression of RA may lead to the implantation of joint endoprostheses, which is associated with a pro-inflammatory increase in IL-6 in the periprosthetic tissue. Biological agents such as sarilumab have been developed to inhibit IL-6-mediated signaling. However, IL-6 signaling blockade should consider the inhibition of inflammatory processes and the regenerative functions of IL-6. This in vitro study investigated whether inhibiting IL-6 receptors can affect the differentiation of osteoblasts isolated from patients with RA. Since wear particles can be generated at the articular surfaces of endoprostheses leading to osteolysis and implant loosening, the potential of sarilumab to inhibit wear particle-induced pro-inflammatory processes should be investigated. Both in monocultures and indirect co-cultures with osteoclast-like cells (OLCs), human osteoblasts were stimulated with 50 ng/mL each of IL-6 + sIL-6R and in combination with sarilumab (250 nM) to characterize cell viability and osteogenic differentiation capacity. Furthermore, the influence of IL-6 + sIL-6R or sarilumab on viability, differentiation, and inflammation was evaluated in osteoblasts exposed to particles. Stimulation with IL-6 + sIL-6R and sarilumab did not affect cell viability. Except for the significant induction of RUNX2 mRNA by IL-6 + sIL-6R and a significant reduction with sarilumab, no effects on cell differentiation and mineralization could be detected. Furthermore, the different stimulations did not affect the osteogenic and osteoclastic differentiation of co-cultured cells. Compared to the osteoblastic monocultures, a decreased release of IL-8 was triggered in the co-culture. Among these, treatment with sarilumab alone resulted in the greatest reduction of IL-8. The co-culture also showed clearly increased OPN concentrations than the respective monocultures, with OPN secretion apparently triggered by the OLCs. Particle exposure demonstrated decreased osteogenic differentiation using different treatment strategies. However, sarilumab administration caused a trend toward a decrease in IL-8 production after stimulation with IL-6 + sIL-6R. The blockade of IL-6 and its pathway have no significant effect on the osteogenic and osteoclastic differentiation of bone cells derived from patients with RA. Nonetheless, observed effects on the reduced IL-8 secretion need further investigation.

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“…Sarilumab is a human anti-IL-6 receptor (IL-6R) monoclonal IgG1 antibody that targets both the membrane-bound and soluble IL-6 receptor forms ( 364 , 365 ). Therefore, sarilumab blocks both the cis- and trans-inflammatory signaling cascades of IL-6 and reduces the activity of pro-inflammatory cytokines and inflammation ( 364 , 365 ). In particular, sarilumab has been shown to reduce HbA1c values after a 24 week treatment period compared with adalimumab in patients with rheumatoid arthritis with or without T2DM ( 366 ) ( Table II ).…”

Section: Therapeutic Interventions On Inflammatory Mediators For the ...mentioning

confidence: 99%

Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review)

Varra,

Varras,

Varra

et al. 2024

Mol Med Rep

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Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co-morbidities, including type-2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non-alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro-inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro-inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low-grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low-grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti-inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein-1, and/or the blockade of pro-inflammatory mediators, such as IL-1β, ΤΝF-α, visfatin, and plasminogen activator inhibitor-1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity-associated metabolic dysfunction.

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Effects of the Interleukin-6 Receptor Blocker Sarilumab on Metabolic Activity and Differentiation Capacity of Primary Human Osteoblasts

Cited by 3 publications

References 46 publications

Determination of Heterogeneous Proteomic and Metabolomic Response in anti-TNF and anti-IL-6 Treatment of Patients with Rheumatoid Arthritis

Determination of Heterogeneous Proteomic and Metabolomic Response in anti-TNF and anti-IL-6 Treatment of Patients with Rheumatoid Arthritis

IL-6-induced response of human osteoblasts from patients with rheumatoid arthritis after inhibition of the signaling pathway

Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review)

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