Myelosuppressive Therapies Significantly Increase Pro-Inflammatory Cytokines and Directly Cause Bone Loss

In chronic inflammatory joint diseases, such as rheumatoid arthritis, there is an important bone loss. Parathyroid hormone-related protein (PTHrP) and related peptides have shown osteoinductive properties in bone regeneration models, but there are no data on inflammatory joint destruction. We have investigated whether the PTHrP (107-111) C-terminal peptide (osteostatin) could control the development of collagen-induced arthritis in mice. Administration of osteostatin (80 or 120 μg/kg s.c.) after the onset of disease decreased the severity of arthritis as well as cartilage and bone degradation. This peptide reduced serum IgG2a levels as well as T cell activation, with the downregulation of RORγt+CD4+ T cells and upregulation of FoxP3+CD8+ T cells in lymph nodes. The levels of key cytokines, such as interleukin(IL)-1β, IL-2, IL-6, IL-17, and tumor necrosis factor-α in mice paws were decreased by osteostatin treatment, whereas IL-10 was enhanced. Bone protection was related to reductions in receptor activator of nuclear factor-κB ligand, Dickkopf-related protein 1, and joint osteoclast area. Osteostatin improves arthritis and controls bone loss by inhibiting immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Our results support the interest of osteostatin for the treatment of inflammatory joint conditions.

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IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2

International Immunology ◽

10.1093/intimm/dxz063 ◽

2019 ◽

Vol 32 (2) ◽

pp. 89-104 ◽

Cited By ~ 3

Author(s):

Asana Kamohara ◽

Hirohito Hirata ◽

Xianghe Xu ◽

Makoto Shiraki ◽

Sakuo Yamada ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bone Resorption ◽

Bone Loss ◽

Inflammatory Cytokines ◽

Immune Complexes ◽

Protein A ◽

Precursor Cells ◽

Osteoclast Precursor ◽

Deficient Mutant ◽

Pro Inflammatory Cytokines

Abstract Staphylococcus aureus is a main pathogen of osteomyelitis and protein A is a virulence factor with high affinity for IgG. In this study, we investigated whether S. aureus affects the differentiation and bone resorption of osteoclasts through the IgG-binding capacity of protein A. Staphylococcus aureus pre-treated with serum or IgG showed marked enhancement in osteoclastogenesis and bone resorption compared to non-treated S. aureus or a protein A-deficient mutant. Blocking of the Fc receptor and deletion of the Fcγ receptor gene in osteoclast precursor cells showed that enhanced osteoclastogenesis stimulated by S. aureus IgG immune complexes (ICs) was mediated by the Fc receptor on osteoclast precursor cells. In addition, osteoclastogenesis stimulated by S. aureus ICs but not the protein A-deficient mutant was markedly reduced in osteoclast precursor cells of Myd88-knockout mice. Moreover, NFATc1, Syk and NF-κB signals were necessary for osteoclastogenesis stimulated by S. aureus ICs. The results suggest the contribution of a of Toll-like receptor 2 (TLR2)-Myd88 signal to the activity of S. aureus ICs. We further examined the expression of pro-inflammatory cytokines that is known to be enhanced by FcγR-TLR cross-talk. Osteoclasts induced by S. aureus ICs showed higher expression of TNF-α and IL-1β, and marked stimulation of proton secretion of osteoclasts activated by pro-inflammatory cytokines. Finally, injection of S. aureus, but not the protein A-deficient mutant, exacerbated bone loss in implantation and intra-peritoneal administration mouse models. Our results provide a novel mechanistic aspect of bone loss induced by S. aureus in which ICs and both Fc receptors and TLR pathways are involved.

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Osteoporosis and Dietary Inflammatory Index

10.5772/intechopen.96772 ◽

2021 ◽

Author(s):

Olga Cvijanović Peloza ◽

Sandra Pavičić Žeželj ◽

Gordana Kenđel Jovanović ◽

Ivana Pavičić ◽

Ana Terezija Jerbić Radetić ◽

...

Keyword(s):

Bone Loss ◽

Chronic Diseases ◽

Inflammatory Cytokines ◽

Eating Habits ◽

Inflammatory Factors ◽

Fat Tissue ◽

Inflammatory Index ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Healthy bones are constantly being renewed and proper nutrition is an important factor in this process. Anti-inflammatory diet is designed to improve health and prevent the occurrence and development of chronic diseases associated with inadequate diet. Proper nutrition is based on the anti-inflammatory pyramid and changes in poor eating habits are the long-term strategy for preventing inflammation and chronic diseases. Inflammatory factors from food may play a role in the development of osteoporosis and an anti-inflammatory diet may be a way to control and reduce long-term inflammation and prevent bone loss. Pro-inflammatory cytokines from the fat tissue, through activation of the RANKL/RANK/OPG system could intervene with bone metabolism in a way of increased bone loss. Therefore the special attention need to be given to obese patients due to twofold risk, one related to pro-inflammatory cytokines release and the other related to the deprivation of the vitamin D in the fat tissue.

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Accelerated Alveolar Bone Loss in Mice Lacking Interleukin-10

Journal of Dental Research ◽

10.1177/154405910308200812 ◽

2003 ◽

Vol 82 (8) ◽

pp. 632-635 ◽

Cited By ~ 61

Author(s):

A. Al-Rasheed ◽

H. Scheerens ◽

D.M. Rennick ◽

H.M. Fletcher ◽

D.N. Tatakis

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Inflammatory Cytokines ◽

Alveolar Bone ◽

Interleukin 10 ◽

Alveolar Bone Loss ◽

Prevotella Intermedia ◽

Pro Inflammatory Cytokines

Interleukin-10 regulates pro-inflammatory cytokines, including those implicated in alveolar bone resorption. We hypothesized that lack of interleukin-10 leads to increased alveolar bone resorption. Male interleukin-10(−/−) mice, on 129/SvEv and C57BL/6J background, were compared with age-, sex-, and strain-matched interleukin-10(+/+) controls for alveolar bone loss. Immunoblotting was used for analysis of serum reactivity against bacteria associated with colitis and periodontitis. Interleukin-10(−/−) mice had significantly greater alveolar bone loss than interleukin-10(+/+) mice (p = 0.006). The 30–40% greater alveolar bone loss in interleukin-10(−/−) mice was evident in both strains, with C57BL/6J interleukin-10(−/−) mice exhibiting the most bone loss. Immunoblotting revealed distinct interleukin-10(−/−) serum reactivity against Bacteroides vulgatus, B. fragilis, Prevotella intermedia, and, to a lesser extent, against B. forsythus. The results of the present study suggest that lack of interleukin-10 leads to accelerated alveolar bone loss.

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Hindlimb unloading causes regional loading-dependent changes in osteocyte inflammatory cytokines that are modulated by exogenous irisin treatment

npj Microgravity ◽

10.1038/s41526-020-00118-4 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Corinne E. Metzger ◽

S. Anand Narayanan ◽

Peter H. Phan ◽

Susan A. Bloomfield

Keyword(s):

Bone Loss ◽

Bone Turnover ◽

Inflammatory Cytokines ◽

Cancellous Bone ◽

Proximal Humerus ◽

Bone Volume ◽

Hindlimb Unloading ◽

Tnf Α ◽

The Impact ◽

Pro Inflammatory Cytokines

Abstract Disuse-induced bone loss is characterized by alterations in bone turnover. Accruing evidence suggests that osteocytes respond to inflammation and express and/or release pro-inflammatory cytokines; however, it remains largely unknown whether osteocyte inflammatory proteins are influenced by disuse. The goals of this project were (1) to assess osteocyte pro-inflammatory cytokines in the unloaded hindlimb and loaded forelimb of hindlimb unloaded rats, (2) to examine the impact of exogenous irisin during hindlimb unloading (HU). Male Sprague Dawley rats (8 weeks old, n = 6/group) were divided into ambulatory control, HU, and HU with irisin (HU + Ir, 3×/week). Lower cancellous bone volume, higher osteoclast surfaces (OcS), and lower bone formation rate (BFR) were present at the hindlimb and 4th lumbar vertebrae in the HU group while the proximal humerus of HU rats exhibited no differences in bone volume, but higher BFR and lower OcS vs. Con. Osteocyte tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17), RANKL, and sclerostin were elevated in the cancellous bone of the distal femur of HU rats vs. Con, but lower at the proximal humerus in HU rats vs. Con. Exogenous irisin treatment increased BFR, and lowered OcS and osteocyte TNF-α, IL-17, RANKL, and sclerostin in the unloaded hindlimb of HU + Ir rats while having minimal changes in the humerus. In conclusion, there are site-specific and loading-specific alterations in osteocyte pro-inflammatory cytokines and bone turnover with the HU model of disuse bone loss, indicating a potential mechanosensory impact of osteocyte TNF-α and IL-17. Additionally, exogenous irisin significantly reduced the pro-inflammatory status of the unloaded hindlimb.

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Cytokine synergy, collagenases and cartilage collagen breakdown

Biochemical Society Symposium ◽

10.1042/bss0700125 ◽

2003 ◽

Vol 70 ◽

pp. 125-133 ◽

Cited By ~ 7

Author(s):

Tim E. Cawston ◽

Jenny M. Milner ◽

Jon B. Catterall ◽

Andrew D. Rowan

Keyword(s):

Matrix Metalloproteinases ◽

Inflammatory Cytokines ◽

Activator Protein 1 ◽

Activator Protein ◽

And Cartilage ◽

Pro Inflammatory Cytokines

We have investigated proteinases that degrade cartilage collagen. We show that pro-inflammatory cytokines act synergistically with oncastatin M to promote cartilage collagen resorption by the up-regulation and activation of matrix metalloproteinases (MMPs). The precise mechanisms are not known, but involve the up-regulation of c-fos, which binds to MMP promoters at a proximal activator protein-1 (AP-1) site. This markedly up-regulates transcription and leads to higher levels of active MMP proteins.

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