Expression of the RANK/RANKL/OPG system in the human intervertebral disc: implication for the pathogenesis of intervertebral disc degeneration

Sano, Tomohiko; Akeda, Koji; Yamada, Jun−ichi; Takegami, Norihiko; Sudo, Takao; Sudo, Akihiro

doi:10.1186/s12891-019-2609-x

Cited by 13 publications

(21 citation statements)

References 39 publications

(58 reference statements)

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“…Receptor activator of nuclear factor-kappa B (RANK) and its ligand RANKL and the decoy receptor osteoprotegerin (OPG) are central regulators of osteoclast development and essential for osteoimmunology [9][10][11][12]. Recent study showed that RANKL/OPG ratio was significantly increased in the gingival tissues surrounding mini-implants in the rat model with Porphyromonas gingivalis LPS inductions [13].…”

Section: Introductionmentioning

confidence: 99%

RANKL blockade alleviates peri-implant bone loss and is enhanced by anti-inflammatory microRNA-146a through TLR2/4 signaling

Pan

Hu²,

Wang³

et al. 2020

Int J Implant Dent

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Background: The present study was to determine the effect of local anti-RANKL antibody administration in the presence or absence of microRNA-146a on ligature-induced peri-implant bone resorption, and the potential role of TLR2/4 signaling in such effect.Results: Titanium implants were placed in the left maxilla alveolar bone 6 weeks after extraction of first and second molars in C57/BL6 wild-type (WT) and TLR2 −/− TLR4 −/− (TLR2/4 KO) mice. Silk ligatures were tied around the implants 4 weeks after implantation. Anti-RANKL antibody (500 μg/mL) with or without microRNA 146a (miR-146a) (100 nM) was injected into palatal gingiva around implant on days 3, 6, and 9 during 2 weeks of ligation period. Bone resorption around the implants was assessed by 2D imaging using area measurement and 3D imaging using micro-computed tomography (μCT). Real-time quantitative PCR (RT-qPCR) was used to determine the peri-implant gingival mRNA expression levels of pro-inflammatory cytokines (TNF-α) and osteoclastogenesis-related cytokines (RANKL). In both WT and TLR2/4 KO mice, the bone resorption around implants was significantly increased in the ligation only group when compared to the non-ligation group, but TLR2/4 KO mice showed significantly less bone loss compared to WT mice after ligation. As expected, gingival injection of anti-RANKL antibody significantly reduced bone loss compared with the ligation only group in both WT and TLR2/4 KO mice. Moreover, injection of miR-146a in addition to anti-RANKL antibody significantly enhanced the inhibition of bone loss in WT mice but not in TLR2/4 KO mice. Gingival mRNA expressions of RANKL were significantly reduced by anti-RANKL antibody treatment in both WT and TLR2/4 KO mice but were not affected by the additional miR-146a treatment. Gingival mRNA expression of TNF-α was significantly reduced by miR-146a treatment in WT mice but not in TLR2/4 KO mice. The number of gingival inflammatory cell infiltration and peri-implant TRAP-positive cell formation was significantly reduced by the additional miR-146a treatment in WT mice but not in TLR2/4 KO mice.Conclusions: This study suggests that anti-inflammatory miR-146a enhance anti-RANKL-induced inhibition of periimplant bone resorption through the regulation of TLR2/4 signaling and inhibition of TNF-α expression.

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Section: Introductionmentioning

confidence: 99%

RANKL blockade alleviates peri-implant bone loss and is enhanced by anti-inflammatory microRNA-146a through TLR2/4 signaling

Pan

Hu²,

Wang³

et al. 2020

Int J Implant Dent

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“…For example, receptor activator of NF-κB ligand (RANKL) is a member of the tumor necrosis factor ligand superfamily, and it is known that RANKL, its signaling receptor (RANK), and its decoy receptor osteoprotegerin (OPG) are key regulators of the production of extracellular matrix remodeling enzymes [10]. Recently, the expression level of the RANK/RANKL/OPG system was found to be upregulated in degenerated human IVD tissues and be associated with in the process of IVD degeneration [11]. More importantly, the upregulation of RANK/RANKL/OPG can result in the biosynthesis of extracellular matrix-degrading enzymes, including matrix metalloprotease-3 (MMP-3) and MMP-13 in degenerated IVD [11].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the expression level of the RANK/RANKL/OPG system was found to be upregulated in degenerated human IVD tissues and be associated with in the process of IVD degeneration [11]. More importantly, the upregulation of RANK/RANKL/OPG can result in the biosynthesis of extracellular matrix-degrading enzymes, including matrix metalloprotease-3 (MMP-3) and MMP-13 in degenerated IVD [11]. On the other hand, neurotrophin is another biological contributor for the progression of IVD degeneration [12].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have suggested that the expression of MMP-3 and MMP-13 by nucleus pulposus cells was significantly upregulated by exogenous RANKL in the presence of IL-1β [11]. This result led us to analyze whether GPR4 have the potential to regulate the expression of MMP-3, MMP13, and ADAMTS-5 in the degenerated IVD-like acidic condition, as these three enzymes are the main catabolic factors of the extracellular matrix of IVD.…”

mentioning

confidence: 96%

“…RANKL interacts with RANK, which is expressed on the membranes of mature osteoclasts and osteoclast precursors, to promote differentiation and activation of osteoclasts. It is reported that the RANK/RANKL/OPG system may play a part in the process of IVD degeneration; RANKL can induce the expression of genes encoding inflammation mediators [10,11]. In the study of Okito et al, they found that GPR4-mediated RANKL expression of osteoblasts in an acidic microenvironment via the cAMP/PKA signaling pathway [25].…”

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confidence: 99%

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Involvement of the G‐Protein‐Coupled Receptor 4 in the Increased Expression of RANK/RANKL/OPG System and Neurotrophins by Nucleus Pulposus Cells under the Degenerated Intervertebral Disc‐Like Acidic Microenvironment

Liu

Zhang

et al. 2020

BioMed Research International

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Intervertebral disc (IVD) degeneration is associated with local inflammation and increased expression of neurotrophins. Acidic microenvironment is believed to cause the progression of IVD degeneration. However, there is a paucity of information regarding the relationship between acidic microenvironment and the inflammation and expression of neurotrophins in IVD. G-protein-coupled receptor 4 (GPR4) is a pH-sensing receptor, which can activate the inflammation and increase the expression levels of nerve growth factor in acidic microenvironment. In this study, culture media with pH 7.2 (representing the normal IVD-like acidic condition) and pH 6.5 (degenerated IVD-like acidic condition) were prepared. The gene and protein expression levels of GPR4 in SD rat nucleus pulposus cells were determined under the acidic conditions. And cyclic AMP (cAMP), the second messenger of GPR4, was assayed. Furthermore, the expression levels of receptor activator of nuclear factor κ B (RANK), RANKL ligand (RANKL), osteoprotegerin (OPG), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were also determined. To clarify the involvement of GPR4 in the upregulation of the expression of RANK/RANKL/OPG system and neurotrophins, gene knockdown and forced expression of GPR4 and inhibiting its downstream cAMP accumulation and Ca2+ mobilization were performed. The alternation of the expression levels of matrix metalloproteinase-3 (MMP-3), MMP-13, and aggrecanase-2 (ADAMTS-5) were evaluated by RT-PCR and western blot. The results showed that GPR4 was expressed in rat nucleus pulposus cells, and the expression was upregulated under the degenerated IVD-like acidic microenvironment. cAMP accumulation levels were increased under the degenerated IVD-like acidic culture conditions. The expression levels of RANK, RANKL, OPG, NGF, and BNDF were significantly upregulated under the degenerated IVD-like acidic microenvironment. GPR4 knockdown and reduction of cAMP by the inhibitor SQ22536 abolished the upregulation of the expression of RANK, RANKL, OPG, NGF, and BNDF under the degenerated IVD-like acidic microenvironment. On the opposite, acidosis-induced cAMP accumulation and upregulation of RANK, RANKL, OPG, NGF, and BNDF were further promoted by GPR4 overexpression. The expression levels of MMP-3, MMP-13, and ADAMTS-5 were upregulated under the degenerated IVD-like acidic condition, which can be promoted or attenuated by GPR4 overexpression or knockdown, respectively. We concluded that GPR4-mediated cAMP accumulation was involved in the increased expression of RANK/RANKL/OPG system and neurotrophins by nucleus pulposus cells under the degenerated IVD-like acidic microenvironment.

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Targeted screening of inflammatory mediators in spontaneous degenerative disc disease in dogs reveals an upregulation of the tumor necrosis superfamily

Bitterli,

Schmid,

Ettinger

et al. 2023

JOR Spine

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BackgroundThe regulation of inflammatory mediators in the degenerating intervertebral disc (IVD) and corresponding ligamentum flavum (LF) is a topic of emerging interest. The study aimed to investigate the expression of a broad array of inflammatory mediators in the degenerated LF and IVD using a dog model of spontaneous degenerative disc disease (DDD) to determine potential treatment targets.MethodsLF and IVD tissues were collected from 22 normal dogs (Pfirrmann grades I and II) and 18 dogs affected by DDD (Pfirrmann grades III and IV). A qPCR gene array was used to investigate the expression of 80 inflammatory genes for LF and IVD tissues, whereafter targets of interest were investigated in additional tissue samples using qPCR, western blot (WB), and immunohistochemistry.ResultsTumor necrosis factor superfamily (TNFSF) signaling was identified as a regulated pathway in DDD, based on the significant regulation (n‐fold ± SD) of various TNFSF members in the degenerated IVD, including nerve growth factor (NGF; −8 ± 10), CD40LG (464 ± 442), CD70 (341 ± 336), TNFSF Ligand 10 (9 ± 8), and RANKL/TNFSF Ligand 11 (85 ± 74). In contrast, TNFSF genes were not significantly affected in the degenerated LF compared to the control LF. Protein expression of NGF (WB) was significantly upregulated in both the degenerated LF (4.4 ± 0.5) and IVD (11.3 ± 5.6) compared to the control group. RANKL immunopositivity was significantly upregulated in advanced stages of degeneration (Thompson grades IV and V) in the nucleus pulposus and annulus fibrosus of the IVD, but not in the LF.ConclusionsDDD involves a significant upregulation of various TNFSF members, with tissue‐specific expression profiles in LF and IVD tissues. The differential involvement of TNFSF members within multiple spinal tissues from the same individual provides new insights into the inflammatory processes involved in DDD and may provide a basis to formulate hypotheses for the determination of potential treatment targets.

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Expression of the RANK/RANKL/OPG system in the human intervertebral disc: implication for the pathogenesis of intervertebral disc degeneration

Cited by 13 publications

References 39 publications

RANKL blockade alleviates peri-implant bone loss and is enhanced by anti-inflammatory microRNA-146a through TLR2/4 signaling

RANKL blockade alleviates peri-implant bone loss and is enhanced by anti-inflammatory microRNA-146a through TLR2/4 signaling

Involvement of the G‐Protein‐Coupled Receptor 4 in the Increased Expression of RANK/RANKL/OPG System and Neurotrophins by Nucleus Pulposus Cells under the Degenerated Intervertebral Disc‐Like Acidic Microenvironment

Targeted screening of inflammatory mediators in spontaneous degenerative disc disease in dogs reveals an upregulation of the tumor necrosis superfamily

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