Osteoimmunology — The hidden immune regulation of bone

Caetano-Lopes, Joana; Canhão, Helena; Fonseca, JE

doi:10.1016/j.autrev.2008.07.038

Cited by 125 publications

(56 citation statements)

References 34 publications

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“…This dynamic process involves a balance between bone-forming osteoblasts, derived from mesenchymal progenitor cells, and bone-resorbing osteoclasts, derived from hematopoietic stem cells (35). A balance of the activity of these cells is required for maintaining normal bone homeostasis (36). The key signaling pathway regulating osteoclast formation is RANKL/RANK pathway.…”

Section: Discussionmentioning

confidence: 99%

Carboxyl Terminus of Hsp70‐Interacting Protein Regulation of Osteoclast Formation in Mice Through Promotion of Tumor Necrosis Factor Receptor–Associated Factor 6 Protein Degradation

Shu

Zhang

et al. 2014

Arthritis & Rheumatology

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Objective Carboxyl terminus of Hsp70-interacting protein (CHIP or STUB1) is an E3 ligase and regulates the stability of several proteins which are involved in tumor growth and metastasis. However, the role of CHIP in bone growth and bone remodeling in vivo has not been reported. The objective of this study is to investigate the role and mechanism of CHIP in regulation of bone mass and bone remodeling. Methods The bone phenotype of Chip−/− mice was examined by histology, histomorphometry and micro-CT analyses. The regulatory mechanism of CHIP on the degradation of TRAF6 and the inhibition of NF-κB signaling was examined by immunoprecipitation (IP), western blotting and luciferase reporter assays. Results In this study, we found that deletion of the Chip gene leads to osteopenic phenotype and increased osteoclast formation. We further found that TRAF6, as a novel substrate of CHIP, is up-regulated in Chip−/− osteoclasts. TRAF6 is critical for RANKL-induced osteoclastogenesis. TRAF6 is an adaptor protein which functions as an E3 ligase to regulate the activation of TAK1 and the I-κB kinase (IKK) and is a key regulator of NF-κB signaling. CHIP interacts with TRAF6 to promote TRAF6 ubiquitination and proteasome degradation. CHIP inhibits p65 nuclear translocation, leading to the repression of the TRAF6-mediated NF-κB transcription. Conclusion CHIP inhibits NF-κB signaling via promoting TRAF6 degradation and plays an important role in osteoclastogenesis and bone remodeling, suggesting that it may be a novel therapeutic target for the treatment of bone loss associated diseases.

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Section: Discussionmentioning

confidence: 99%

Carboxyl Terminus of Hsp70‐Interacting Protein Regulation of Osteoclast Formation in Mice Through Promotion of Tumor Necrosis Factor Receptor–Associated Factor 6 Protein Degradation

Shu

Zhang

et al. 2014

Arthritis & Rheumatology

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“…During physiologic conditions, this dynamic bone remodeling is controlled by precise orchestration of osteoblasts and osteoclasts. 1 An imbalance in this homeostasis is linked to metabolic bone diseases, such as osteoporosis and inflammatory bone diseases. 2 During chronic inflammatory conditions, such as arthritis and periodontitis, bone homeostasis is skewed towards osteoclast-induced bone resorption.…”

Section: Introductionmentioning

confidence: 99%

“…2 During chronic inflammatory conditions, such as arthritis and periodontitis, bone homeostasis is skewed towards osteoclast-induced bone resorption. 1 …”

Section: Introductionmentioning

confidence: 99%

TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions

Muthukuru

Darveau

2014

Bone Res

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Toll-like receptor (TLR)-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 (P3C) and Escherichia coli lipopolysaccharide (EcLPS) were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism (Pg1690) or TLR4 antagonism (Pg1449) and mutant E. coli LPS (LPxE/LPxF/WSK) were used. IL-1β, SH2-containing inositol phosphatase-1 (SHIP1) that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane (3AC) was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 (with SHIP1 activity) and mutant TLR4 ligands could enhance osteogenesis.

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“…The production of OPG by a variety of tissues (such as cardiovascular system, bone and immune cells) is also modulated by various cytokines, hormones and drugs. To notice, glucocorticoids, PTH and basic fibroblast growth factor might suppress OPG expression [92], [93].…”

Section: Discussionmentioning

confidence: 98%

Bone Disease in Newly Diagnosed Lupus Nephritis Patients

et al. 2014

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IntroductionBone loss in Lupus Nephritis (LN) patients is common and multifactorial. The aim of this study was to evaluate the bone status of newly diagnosed LN patients and their correlation with inflammatory factors involved in LN physiopathology.MethodsWe studied 15 pre-menopausal patients with ≤2 months of diagnosed SLE and LN. Patients with prior kidney or bone disease were excluded. In addition to biochemical evaluation (including 25-hydroxyvitamin D3 [25(OH)D] and Monocyte Chemotactic Protein (MCP1) dosage), we performed bone biopsies followed by osteoblast culture, histomorphometric and immunohistochemistry analysis.ResultsLN patients presented a mean age of 29.5±10 years, a proteinuria of 4.7±2.9 g/day and an estimated glomerular filtration rate (GFR) of 37(31–87) ml/min/1,73 m2. They were on glucocorticoid therapy for 34±12 days. All patients presented vitamin D insufficiency (9.9±4.4 ng/ml, range 4–20). Urinary MCP1 correlated negatively with 25(OH)D (r = −0.53, p = 0.003) and positively with serum deoxypyridinoline (r = 0.53, p = 0.004). Osteoblasts isolated from LN bone biopsies presented a significantly higher expression of MCP-1 when compared to controls (32.0.±9.1 vs. 22.9±5.3 mean fluorescence intensities, p = 0.01). LN patients presented a significantly reduced osteoid volume, osteoid thickness, osteoid surface, mineralization surface and bone formation rate, associated with an increased eroded surface and osteoclast surface. Patient’s bone specimens demonstrated a reduced immunostaining for osteoprotegerin (0.61±0.82 vs. 1.08±0.50%, p = 0.003), and an increased expression of Receptor Activator of NF-κB ligand (RANKL) (1.76±0.92 vs. 0.41±0.28%, p<0.001) when compared to controls.DiscussionNewly diagnosed LN patients presented a significant disturbance in bone metabolism, characterized by an impaired bone formation and mineralization, associated with an increase in resorption parameters. Glucocorticoid use, vitamin D insufficiency and inflammation might be involved in the physiopathology of bone metabolism disturbance.

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Osteoimmunology — The hidden immune regulation of bone

Cited by 125 publications

References 34 publications

Carboxyl Terminus of Hsp70‐Interacting Protein Regulation of Osteoclast Formation in Mice Through Promotion of Tumor Necrosis Factor Receptor–Associated Factor 6 Protein Degradation

Carboxyl Terminus of Hsp70‐Interacting Protein Regulation of Osteoclast Formation in Mice Through Promotion of Tumor Necrosis Factor Receptor–Associated Factor 6 Protein Degradation

TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions

Bone Disease in Newly Diagnosed Lupus Nephritis Patients

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