IL-23, but not IL-12, plays a critical role in inflammation-mediated bone disorders

Xu, Jiajia; Li, Jiao; Hu, Y.; Dai, Kerong; Gan, Yaokai; Zhao, Jingyu; Huang, Mingjian; Zhang, Xiaoling

doi:10.7150/thno.41378

Cited by 11 publications

(11 citation statements)

References 59 publications

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“…An interesting question for future investigations would be whether the Pro-B cells can transdifferentiate to osteoclasts in the absence of monocytes, and whether this process is affected by inflammatory conditions which are known to stimulate osteoclastogenesis 57 , 58 . In our primary cultures, we could trace the differentiation of B cells to osteoclasts, but we cannot completely rule out the possibility that sporadic monocytes that did not reach the level of detection by flow cytometry were still present.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Deshet-Unger¹,

Kim²,

Ben‐Califa³

et al. 2020

Theranostics

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Erythropoietin (EPO) is a key regulator of erythropoiesis. However, EPO receptors (EPO-Rs) are also expressed on non-erythroid cell types, including myeloid and bone cells. Immune cells also participate in bone homeostasis. B cells produce receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG), two pivotal regulators of bone metabolism. Here we explored the ability of B cells to transdifferentiate into functional osteoclasts and examined the role of EPO in this process in a murine model. Methods: We have combined specifically-designed experimental mouse models and in vitro based osteoclastogenesis assays, as well as PCR analysis of gene expression. Results: (i) EPO treatment in vivo increased RANKL expression in bone marrow (BM) B cells, suggesting a paracrine effect on osteoclastogenesis; (ii) B cell-derived osteoclastogenesis occured in vivo and in vitro, as demonstrated by B cell lineage tracing in murine models; (iii) B-cell-derived osteoclastogenesis in vitro was restricted to Pro-B cells expressing CD115/CSF1-R and is enhanced by EPO; (iv) EPO treatment increased the number of B-cell-derived preosteoclasts (β3 + CD115 + ), suggesting a physiological rationale for B cell derived osteoclastogenesis; (v) finally, mice with conditional EPO-R knockdown in the B cell lineage (cKD) displayed a higher cortical and trabecular bone mass. Moreover, cKD displayed attenuated EPO-driven trabecular bone loss, an effect that was observed despite the fact that cKD mice attained higher hemoglobin levels following EPO treatment. Conclusions: Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling and suggests their involvement in the regulation of bone homeostasis and possibly in EPO-stimulated erythropoietic response. Importantly, we present here for the first time, histological evidence for B cell-derived osteoclastogenesis in vivo .

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Section: Discussionmentioning

confidence: 99%

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Deshet-Unger¹,

Kim²,

Ben‐Califa³

et al. 2020

Theranostics

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“…Moreover, IL-12 and IL-23 indirectly inhibit osteoblastogenesis by stimulating CD4 + T cells [ 108 ]. Enhanced bone formation IL-12p40 -deficient mice was protective against age-related bone loss [ 109 ]. Collectively, IL-12 and IL-23 are potential anti-osteoblastogenic cytokines.…”

Section: Cytokine Regulation Of Osteoblastogenesismentioning

confidence: 99%

Regulation of Osteoblast Differentiation by Cytokine Networks

Amarasekara

Kim

Rho

2021

IJMS

188

137

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Osteoblasts, which are bone-forming cells, play pivotal roles in bone modeling and remodeling. Osteoblast differentiation, also known as osteoblastogenesis, is orchestrated by transcription factors, such as runt-related transcription factor 1/2, osterix, activating transcription factor 4, special AT-rich sequence-binding protein 2 and activator protein-1. Osteoblastogenesis is regulated by a network of cytokines under physiological and pathophysiological conditions. Osteoblastogenic cytokines, such as interleukin-10 (IL-10), IL-11, IL-18, interferon-γ (IFN-γ), cardiotrophin-1 and oncostatin M, promote osteoblastogenesis, whereas anti-osteoblastogenic cytokines, such as tumor necrosis factor-α (TNF-α), TNF-β, IL-1α, IL-4, IL-7, IL-12, IL-13, IL-23, IFN-α, IFN-β, leukemia inhibitory factor, cardiotrophin-like cytokine, and ciliary neurotrophic factor, downregulate osteoblastogenesis. Although there are gaps in the body of knowledge regarding the interplay of cytokine networks in osteoblastogenesis, cytokines appear to be potential therapeutic targets in bone-related diseases. Thus, in this study, we review and discuss our osteoblast, osteoblast differentiation, osteoblastogenesis, cytokines, signaling pathway of cytokine networks in osteoblastogenesis.

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“…Moreover, ustekinumab treatment significantly increased mRNA expression of CREB3L1 gene encoding a transcription factor involved in bone formation ( 43 ); CREB3L1 deficiency can cause severe osteogenesis imperfecta ( 44 ). Animal studies already suggested a role for IL-12p40 in bone remodeling, since IL-12p40 depletion in mice stimulated bone regeneration and increased bone mass, while IL-12p35 depletion (solely targeting IL-12) impaired bone regeneration and increased bone loss ( 45 ). Clinically, ustekinumab-treated PsA patients had significantly lower radiographic progression (i.e., lower Sharp/van der Heijde score on joint space narrowing and erosions) than the placebo-treated group ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

et al. 2021

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Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear.Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients.Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR).Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis.Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.

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IL-23, but not IL-12, plays a critical role in inflammation-mediated bone disorders

Cited by 11 publications

References 59 publications

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Erythropoietin receptor in B cells plays a role in bone remodeling in mice

Regulation of Osteoblast Differentiation by Cytokine Networks

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

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