Histological Evidence of Increased Osteoclast Cell Number and Asymmetric Bone Resorption Activity in the Tibiae of Interleukin-6-Deficient Mice

Liu, Hongrui; Feng, Wei; Yimin,; Cui, Jian; Lv, Shengyu; Hasegawa, Tomoka; Sun, Bei; Li, Juan; Oda, Kimimitsu; Amizuka, Norio; Li, Minqi

doi:10.1369/0022155414537830

Cited by 20 publications

(14 citation statements)

References 40 publications

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“…We have previously examined the impact of IL-6-deficiency on osteoclast formation in vivo and found that depletion of IL-6 in mice resulted in increased numbers of osteoclasts with attenuated resorptive activity, indicating separate regulation of the number and function of osteoclasts by IL-6 23 . This study therefore aimed to investigate the influence of IL-6 and sIL-6R on gradient concentrations of RANKL-induced osteogenesis and to identify the potential underlying mechanisms.…”

mentioning

confidence: 99%

Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways

Feng

Liu

Luo

et al. 2017

Sci Rep

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Interleukin (IL)-6 is known to indirectly enhance osteoclast formation by promoting receptor activator of nuclear factor kappa-B ligand (RANKL) production by osteoblastic/stromal cells. However, little is known about the direct effect of IL-6 on osteoclastogenesis. Here, we determined the direct effects of IL-6 and its soluble receptor (sIL-6R) on RANKL-induced osteoclast formation by osteoclast precursors in vitro. We found IL-6/sIL-6R significantly promoted and suppressed osteoclast differentiation induced by low- (10 ng/ml) and high-level (50 ng/ml) RANKL, respectively. Using a bone resorption pit formation assay, expression of osteoclastic marker genes and transcription factors confirmed differential regulation of RANKL-induced osteoclastogenesis by IL-6/sIL-6R. Intracellular signaling transduction analysis revealed IL-6/sIL-6R specifically upregulated and downregulated the phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), ERK (extracellular signal–regulated kinase) and JNK (c-Jun N-terminal kinase) induced by low- and high level RANKL, respectively. Taken together, our findings demonstrate that IL-6/sIL-6R differentially regulate RANKL-induced osteoclast differentiation and activity through modulation of NF-κB, ERK and JNK signaling pathways. Thus, IL-6 likely plays a dual role in osteoclastogenesis either as a pro-resorption factor or as a protector of bone, depending on the level of RANKL within the local microenvironment.

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confidence: 99%

Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways

Feng

Liu

Luo

et al. 2017

Sci Rep

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“…GL has a long history of well-known anti-inflammatory effects (53–55), and studies show that it can inhibit the chemoattractant and mitogenic activity of HMGB1 by direct binding (52, 56). It has also been administered to patients with hepatitis B and C and is considered to be safe for human consumption (52, 57, 58), but GL may have off-target effects other than inhibition of HMGB1. The side effect of GL is mainly from its metabolic product glycyrrhetic acid after oral ingestion and catalyzed by bacteria in gut(59), which is irrelevant to IP injection of GL that we used in this study.…”

Section: Discussionmentioning

confidence: 99%

HMGB1 mediates the development of tendinopathy due to mechanical overloading

Zhao

Zhang

Nie

et al. 2019

Preprint

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15 Mechanical overloading is a major cause of tendinopathy, but the underlying pathogenesis of 16 tendinopathy is unclear. Here we report that high mobility group box1 (HMGB1) is released to 17 the tendon extracellular matrix and initiates an inflammatory cascade in response to mechanical 18 overloading in a mouse model. Moreover, administration of glycyrrhizin (GL), a naturally 19 occurring triterpene and a specific inhibitor of HMGB1, the tendon's inflammatory reactions.20 Also, while prolonged mechanical overloading in the form of long-term intensive treadmill 21 running induces Achilles tendinopathy in mice, administration of GL completely blocks the 22 tendinopathy development. Additionally, mechanical overloading of tendon cells in vitro induces 23 HMGB1 release to the extracellular milieu, thereby eliciting inflammatory and catabolic 24 responses as marked by increased production of prostaglandin E 2 (PGE 2 ) and matrix 25 metalloproteinase-3 (MMP-3) in tendon cells. Application of GL abolishes the cellular 26 inflammatory/catabolic responses. Collectively, these findings point to HMGB1 as a key 27 molecule that is responsible for the induction of tendinopathy due to mechanical overloading 28 placed on the tendon. 29 Keywords: Mechanical overloading, HMGB1, tendinopathy, tendon inflammation, tendon 30 degeneration, glycyrrhizin 31 32 Introduction 33 34Tendinopathy, a debilitating chronic tendon disorder, is manifested in clinical settings by 35 a combination of pain, swelling, compromised tendon structure, and rupture (1). Tendinopathy, 36 which involves tendon inflammation and degeneration, affects healthy individuals during their 37 active and productive years of life resulting in tremendous healthcare costs and economic impact 38 due to work-loss (2, 3). In particular, insertional tendinopathy, which is common in young 39 athletes, often occurs in the tendon proper proximal to the insertion into the heel bone and 40 accounts for about 20% of Achilles tendon disorders (4). It is well established that while normal 41 physiological loading is essential for tendon homeostasis, mechanical overloading induces the 42 development of tendinopathy, characterized by disorganized matrix, reduced numbers and 43 rounding of tendon cells, fibrocartilaginous change, and neovascularization (5, 6). A current 44 concept on the mechanisms of tendinopathy is that repetitive loading may lead to a 45 mechanobiological over-stimulation of tendon cells resulting in an imbalance between the 46 synthesis and breakdown of matrix proteins, especially collagen (7-9). The resulting mismatch is 47 a continuous loss of collagen in the tendon by repetitive loading with insufficient recovery time, 48 which initiates a catabolic degenerative response that leads to tendinopathy (6, 10). 50It is now recognized that inflammation is part of tendinopathy and could lead to tendon 51 degeneration that occurs at late stages of tendinopathy (11)(12)(13). Under excessive mechanical 52 loading, abnormal levels of proinflammatory mediators may be rel...

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“…Bone formation is reduced, and bone remodeling is impaired in IL-6 knockout (IL-6 - / - ) mice, 70 and Harris and associates found that orbital spaceflight caused impaired osteoblast function associated with a reduction IL-6 mRNA expression. 71 Using cultures of murine osteoblasts, osteocytes, osteoclast precursors, and compressive cyclic forces, Hao and associates found that IL-6 + sIL-6R increased osteocyte-mediated osteoblast differentiation and inhibited osteoclastogenesis and osteoclast differentiation under mechanical loading via STAT3 and extracellular signal-regulated kinase (ERK) signaling pathways 72 …”

Section: Il-6 and Bone Homeostasismentioning

confidence: 99%

IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight

Smith

2018

npj Microgravity

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We have previously reported that exercise-related secretion of IL-6 by peripheral blood mononuclear cells is proportionate to body weight, suggesting that IL-6 is gravisensitive and that suboptimal production of this key cytokine may contribute to homeostatic dysregulations that occur during spaceflight. This review details what is known about the role of this key cytokine in innate and adaptive immunity, hematopoiesis, and in bone, muscle and metabolic homeostasis on Earth and in the microgravity of space and suggests an experimental approach to confirm or disavow the role of IL-6 in space-related dysregulations.

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Histological Evidence of Increased Osteoclast Cell Number and Asymmetric Bone Resorption Activity in the Tibiae of Interleukin-6-Deficient Mice

Cited by 20 publications

References 40 publications

Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways

Combination of IL-6 and sIL-6R differentially regulate varying levels of RANKL-induced osteoclastogenesis through NF-κB, ERK and JNK signaling pathways

HMGB1 mediates the development of tendinopathy due to mechanical overloading

IL-6 and the dysregulation of immune, bone, muscle, and metabolic homeostasis during spaceflight

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