Inflammatory bone loss: pathogenesis and therapeutic intervention

Redlich, Kurt; Smolen, Josef S

doi:10.1038/nrd3669

Cited by 634 publications

(594 citation statements)

References 238 publications

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“…For this, we used three mouse models that recapitulate different pathological situations associated with increased osteoclast activation: post-menopause osteoporosis 14 , chronic inflammation 15 and cancer metastasis to the bone 16 .…”

Section: C21 Reversibly Disrupts Podosome Organization In Osteoclastsmentioning

confidence: 99%

“…We then evaluated the effect of C21 on bone loss associated with rheumatoid arthritis, a disease characterized by chronic inflammation and synovial hyperplasia in joints that ultimately leads to systemic osteoporosis stimulated by proinflammatory cytokines 15 . It can be modelled by immunization of susceptible DBA/ 1 mouse strain with type II collagen, the major protein component of articular cartilage 18 (Fig.…”

Section: Dock5 Inhibition Prevents Inflammation-induced Bone Lossmentioning

confidence: 99%

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Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

et al. 2015

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Osteoporosis is caused by excessive activity of bone-degrading osteoclasts over bone-forming osteoblast. Standard antiosteolytic treatments inhibit bone resorption by inducing osteoclast loss, with the adverse effect of hindering also bone formation. Formation of the osteoclast sealing zone requires Dock5, a guanine nucleotide exchange factor for the small GTPase Rac, and C21, a chemical inhibitor of Dock5, decreases bone resorption by cultured osteoclasts. Here we show that C21 directly inhibits the exchange activity of Dock5 and disrupts osteoclast podosome organization. Remarkably, C21 administration protects mice against bone degradation in models recapitulating major osteolytic diseases: menopause, rheumatoid arthritis and bone metastasis. Furthermore, C21 administration does not affect bone formation and is not toxic. Our results validate the pharmacological inhibition of Dock5 as a novel therapeutic route for fighting osteolytic diseases while preserving bone formation.

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Section: C21 Reversibly Disrupts Podosome Organization In Osteoclastsmentioning

confidence: 99%

Section: Dock5 Inhibition Prevents Inflammation-induced Bone Lossmentioning

confidence: 99%

Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

et al. 2015

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“…Many signaling pathways have been proposed to mediate inflammatory bone loss by perturbing the balance of osteoclast and osteoblast activity (3). Tumor necrosis factor (TNF) is a proinflammatory cytokine that is upregulated in many chronic inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Meta‐Analysis of Tumor Necrosis Factor Inhibitors and Glucocorticoids on Bone Density in Rheumatoid Arthritis and Ankylosing Spondylitis Trials

Siu

Haraoui

Bissonnette

et al. 2015

Arthritis Care & Research

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Objective. To examine the impact of antirheumatic drugs on bone mineral density (BMD) in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis using a systematic review. Methods. Electronic databases were systematically searched for randomized controlled trials. Studies were grouped based on disease, treatment, and site of BMD measurement. Change in BMD (DBMD) from baseline to end of study was recorded. Standardized mean difference (SMD) of DBMD between treatment and controls was standardized for meta-analyses and 95% confidence intervals (95% CIs) were calculated. Results. Treatment effects on BMD were not the primary outcomes of the trials. Thirteen studies were eligible (11 RA, 2 AS, 0 PsA, and 0 psoriasis). For RA, significantly less hand bone loss was seen with tumor necrosis factor inhibitors (TNFi; SMD DBMD 0.33 [95% CI 0.13, 0.53], P 5 0.001, I 2 5 0%) and glucocorticoids (SMD DBMD 0.51 [95% CI 0.20, 0.81], P 5 0.001, I 2 5 0%). TNFi had no significant effect on lumbar spine and hip BMD. Glucocorticoids were associated with a negative effect on lumbar spine (SMD DBMD 20.30 [95% CI 20.55,20.04], P 5 0.02, I 2 5 52%), but not hip BMD. For AS, a significant increase in BMD was seen with TNFi at the lumbar spine (SMD DBMD 0.96 [95% CI 0.64, 1.27], P < 0.001, I 2 5 16%) and hip (SMD DBMD 0.38 [95% CI 0.13, 0.62], P 5 0.003, I 2 5 0%). Data were insufficient to perform meta-analyses in PsA and psoriasis or for other antirheumatic drugs. Conclusion. In RA, TNFi and glucocorticoids appeared to attenuate hand bone loss. TNFi did not impact lumbar spine and hip BMD and glucocorticoids had negative effects on lumbar spine and no effect on hip BMD. In AS, TNFi was associated with improved lumbar spine and hip BMD.

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“…The continued inflammatory state seen in the +Inc/-Abx group is not a favorable state for the bone regeneration. 32 However, the anti-inflammatory cytokine IL-10 is upregulated in the +Inc/-Abx group, possibly in an attempt to suppress the proliferation of inflammatory T-lymphocytes. 33 The RANKL:OPG ratio reflects bone remodeling and homeostasis by comparing the relative expression of RANKL, an osteoclast inducer, and OPG, a decoy receptor, that prevents RANKL from activating osteoclasts.…”

Section: Discussionmentioning

confidence: 98%

Effects of Local Antibiotic Delivery from Porous Space Maintainers on Infection Clearance and Induction of an Osteogenic Membrane in an Infected Bone Defect

Shah

Smith

Tatara

et al. 2017

Tissue Engineering Part A

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Reconstruction of large bone defects can be complicated by the presence of both infection and local antibiotic administration. This can be addressed through a two-stage reconstructive approach, called the Masquelet technique, that involves the generation of an induced osteogenic membrane over a temporary poly(methyl methacrylate) (PMMA) space maintainer, followed by definitive reconstruction after the induced membrane is formed. Given that infection and antibiotic delivery each have independent effects on local tissue response, the objective of this study is to evaluate the interaction between local clindamycin release and bacterial contamination with regards to infection prevention and the restoration of pro-osteogenic gene expression in the induced membrane. Porous PMMA space maintainers with or without clindamycin were implanted in an 8 mm rat femoral defect model with or without Staphylococcus aureus inoculation for 28 days in a full-factorial study design (four groups, n = 8/group). Culture results demonstrated that 8/8 animals in the inoculated/no antibiotic group were infected at 4 weeks, which was significantly reduced to 1/8 animals in the inoculated/antibiotic group. Quantitative polymerase chain reaction analysis demonstrated that clindamycin treatment restores inflammatory cytokine and growth factor expression to the same levels as the no inoculation/no antibiotic group, demonstrating that clindamycin can ameliorate the negative effects of bacterial inoculation and does not itself negatively impact the expression of important cytokines. Main effect analysis shows that bacterial inoculation and clindamycin treatment have independent and interacting effects on the gene expression profile of the induced membrane, further highlighting that antibiotics play an important role in the regeneration of infected defects apart from their antimicrobial properties.

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Inflammatory bone loss: pathogenesis and therapeutic intervention

Cited by 634 publications

References 238 publications

Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

Meta‐Analysis of Tumor Necrosis Factor Inhibitors and Glucocorticoids on Bone Density in Rheumatoid Arthritis and Ankylosing Spondylitis Trials

Effects of Local Antibiotic Delivery from Porous Space Maintainers on Infection Clearance and Induction of an Osteogenic Membrane in an Infected Bone Defect

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