Bone Damage in Rheumatoid Arthritis: Mechanistic Insights and Approaches to Prevention

Karmakar, Sougata; Kay, Jonathan; Gravallese, Ellen M.

doi:10.1016/j.rdc.2010.03.003

Cited by 171 publications

(153 citation statements)

References 124 publications

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“…In bone marrow cultures from ovariectomized mice, the increased osteoclast formation could be prevented by 17␤-estradiol or by a neutralizing IL-6-antibody (28,29). It was also reported that IL-6 stimulates RANKL expression in osteoblasts (30), which induces osteoclastogenesis. On the other hand, it was shown that IL-6 inhibits RANKL-induced osteoclast formation and bone resorption (31).…”

Section: Discussionmentioning

confidence: 94%

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Thaler

Agsten

Spitzer

et al. 2011

Journal of Biological Chemistry

107

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Elevated homocysteine (Hcys) serum levels represent a risk factor for several chronic pathologies, including cardiovascular disease, atherosclerosis, and chronic renal failure, and affect bone development, quality, and homeostasis. Hcys influences the formation of a stable bone matrix directly through the inhibition of the collagen cross-linking enzyme lysyl oxidase (Lox) and, as we have shown recently, by repressing its mRNA expression. The aim of this study was to investigate the mechanisms involved in this process. Epidemiological studies have shown that high homocysteine (Hcys) 2 serum levels represent a risk factor for several chronic disorders such as cardiovascular disease, atherosclerosis, chronic renal failure, diabetes, or the metabolic syndrome (1, 2). Moreover, hyperhomocysteinemia is known to affect bone development and homeostasis (3-6). Hcys has been shown to interfere with post-translational modifications of collagen directly by inhibiting lysyl oxidase (Lox) (7) and indirectly by down-regulation of its mRNA expression and of other genes involved in collagen cross-linking. Enzymatic inhibition or mRNA down-regulation of Lox results in changes in collagen cross-linking pattern in vitro (8 -10) and in vivo resulting in decreased bone quality (11)(12)(13). In this context, we have recently reported a correlation between plasma Hcys levels and a collagen cross-link ratio in forming trabecular surfaces in human bone (14).Lysyl oxidase was also identified as a phenotypic suppressor of the ras oncogene in H-ras-transformed NIH3T3 fibroblasts. In this transformed cell line, H-ras participates in an elaborate pathway attenuating the expression of Lox and of many other genes by CpG methylation on DNA. These genes are reactivated by treatment with azacytidine, an inhibitor of DNA (cytosine-5)-methyltransferases. Methylation of cytosine-guanine dinucleotides (CpGs) on DNA is an important epigenetic mechanism involved in the selective regulation of gene expression and in the stabilization of chromatin, thus controlling tissue development and pathogenesis. Aberrant CpG methylation of specific genes is often found in many tumors and tumorigenic cell lines (15).Besides its role as inhibitor of collagen cross-linking, Hcys is also known to play a role in epigenetic gene regulation being directly involved in the DNA methylation process. Hcys represents a methyl group carrier involved in the S-adenosylmethionine-S-adenosylhomocysteine methylation cycle. Here, Hcys is remethylated to methionine, which is further activated to S-adenosylmethionine, the methyl donor in DNA methylation. S-Adenosylmethionine converts to S-adenosylhomocysteine after DNA methylation. Hydrolysis of S-adenosylhomocysteine to homocysteine completes the cycle (16).

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Section: Discussionmentioning

confidence: 94%

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Thaler

Agsten

Spitzer

et al. 2011

Journal of Biological Chemistry

107

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“…over bone formation (10,(13)(14)(15). IL-17 is a major cytokine driving osteoclastogenesis leading to bone resorption (8,12,26).…”

mentioning

confidence: 99%

Celastrus and Its Bioactive Celastrol Protect against Bone Damage in Autoimmune Arthritis by Modulating Osteoimmune Cross-talk

Nanjundaiah

Venkatesha

et al. 2012

Journal of Biological Chemistry

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Background: Arthritis is characterized by bone and cartilage destruction. Many conventional drugs suppress inflammation but not bone damage. Hence, new therapeutic agents are sought. Results: Celastrus and its bioactive component celastrol inhibit osteoclastogenesis by controlling its mediators and their inducers/effectors. Conclusion: Celastrus/celastrol controls inflammation-driven bone resorption by regulating the osteoimmune cross-talk. Significance: Celastrus and celastrol are promising adjuncts to conventional drugs for arthritis treatment.

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“…Osteoclasts form where pannus tissue interfaces with periarticular bone and mediate bone erosions (reviewed in ref. 20). Data supporting this conclusion stem from studies where inflammatory arthritis was induced in rodents in either a genetically osteoclastdeficient background or concomitant with systemic administration of osteoprotegerin (OPG), a decoy receptor and inhibitor of RANKL (21)(22)(23).…”

Section: Inflammatory Arthritis -Dysregulation Of Bone Remodeling Ranmentioning

confidence: 99%

Osteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection

Jones¹,

Glimcher²,

Aliprantis³

2011

J. Clin. Invest.

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Over the past decade and a half, the biomedical community has uncovered a previously unappreciated reciprocal relationship between cells of the immune and skeletal systems. Work in this field, which has been termed "osteoimmunology," has resulted in the development of clinical therapeutics for seemingly disparate diseases linked by the common themes of inflammation and bone remodeling. Here, the important concepts and discoveries in osteoimmunology are discussed in the context of the diseases bridging these two organ systems, including arthritis, osteoporosis, cancer, and infection, and the targeted treatments used by clinicians to combat them.

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Bone Damage in Rheumatoid Arthritis: Mechanistic Insights and Approaches to Prevention

Cited by 171 publications

References 124 publications

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Celastrus and Its Bioactive Celastrol Protect against Bone Damage in Autoimmune Arthritis by Modulating Osteoimmune Cross-talk

Osteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection

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