scholarly journals Functional Block of Interleukin-6 Reduces a Bone Pain Marker But Not Bone Loss in Hindlimb-Unloaded Mice

2020 ◽  
Vol 21 (10) ◽  
pp. 3521 ◽  
Author(s):  
Hiroki Wakabayashi ◽  
Gaku Miyamura ◽  
Nobuto Nagao ◽  
Sho Kato ◽  
Yohei Naito ◽  
...  
Keyword(s):  
Bone Loss ◽  
Interleukin 6 ◽  
Inhibitory Effect ◽  
Mechanical Hyperalgesia ◽  
Tail Suspension ◽  
Micro Computed Tomography ◽  
Drg Neurons ◽  
Calcitonin Gene ◽  
Proximal Tibial Metaphyses ◽  
Von Frey Filaments

Interleukin-6 (IL-6) is widely accepted to stimulate osteoclasts. Our aim in this study was to examine whether the inhibitory effect of IL-6 on bone loss and skeletal pain associated with osteoporosis in hindlimb-unloaded (HU) mice in comparison with bisphosphonate. Eight-week-old male ddY mice were tail suspended for 2 weeks. Starting immediately after reload, vehicle (HU group), alendronate (HU-ALN group), or anti-IL-6 receptor antibody (HU-IL-6i group) was injected subcutaneously. After a 2-week treatment, pain-related behavior was examined using von Frey filaments. The bilateral distal femoral and proximal tibial metaphyses were analyzed three-dimensionally with micro-computed tomography. Calcitonin gene-related peptide (CGRP) expressions in dorsal root ganglion (DRG) neurons innervating the hindlimbs were examined using immunohistochemistry. HU mice with tail suspension developed bone loss. The HU mice showed mechanical hyperalgesia in the hindlimbs and increased CGRP immunoreactive neurons in the L3-5 DRG. Treatment with IL-6i and ALN prevented HU-induced mechanical hyperalgesia and upregulation of CGRP expressions in DRG neurons. Furthermore, ALN but not IL-6i prevented HU-induced bone loss. In summary, treatment with IL-6i prevented mechanical hyperalgesia in hindlimbs and suppressed CGRP expressions in DRG neurons of osteoporotic models. The novelty of this research suggests that IL-6 is one of the causes of immobility-induced osteoporotic pain regardless improvement of bone loss.

scholarly journals Teriparatide improves pain-related behavior and prevents bone loss in ovariectomized mice

2019 ◽  
Vol 28 (1) ◽  
pp. 230949901989319 ◽  
Author(s):  
Sho Kato ◽  
Hiroki Wakabayashi ◽  
Taro Nakagawa ◽  
Gaku Miyamura ◽  
Yohei Naito ◽  
...  
Keyword(s):  
Bone Loss ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Inhibitory Effect ◽  
Mechanical Hyperalgesia ◽  
Drg Neurons ◽  
Ovariectomized Mice ◽  
Hind Limbs ◽  
Transient Receptor

Purpose: The aim of this study was to examine the inhibitory effect of teriparatide (TPTD) on pain and on bone loss in ovariectomized (OVX) mice. The mechanism of osteoporotic pain in OVX mice was evaluated through an examination of pain-related behavior as well as immunohistochemical examinations. Methods: Eight-week-old female ddY mice were OVX and assigned to one of three groups: (1) OVX mice treated with vehicle (OVX), (2) OVX mice treated with teriparatide (OVX-TPTD), or (3) SHAM-operated mice treated with vehicle (SHAM). Starting immediately after surgery, vehicle or TPTD was injected subcutaneously. After a 4-week treatment, mechanical sensitivity was tested using von Frey filaments. The proximal tibial metaphyses were analyzed three-dimensionally by microcomputed tomography (μCT). Calcitonin gene-related peptide (CGRP) and transient receptor potential channel vanilloid 1 (TRPV1) expressions in L3–5 dorsal root ganglion (DRG) neurons were examined using immunohistochemistry. Results: Ovariectomy induced bone loss and mechanical hyperalgesia in the hind limbs with upregulation of CGRP and TRPV1 expressions in DRG neurons innervating the hind limbs. Bone loss was prevented more effectively in the OVX-TPTD mice than in the OVX mice. Furthermore, mechanical hyperalgesia and upregulation of CGRP and TRPV1 expressions were significantly lower in the OVX-TPTD mice than in the OVX mice. Conclusion: TPTD treatment prevented ovariectomy-induced bone loss and ovariectomy-induced mechanical hyperalgesia in hind limbs, and it suppressed CGRP and TRPV1 expressions in DRG neurons. These results suggest that TPTD is useful for the treatment of osteoporotic pain in postmenopausal women.

scholarly journals CTLA-4Ig Improves Hyperalgesia in a Mouse Model of Osteoporosis

2020 ◽  
Vol 21 (24) ◽  
pp. 9479
Author(s):  
Nobuto Nagao ◽  
Hiroki Wakabayashi ◽  
Gaku Miyamura ◽  
Sho Kato ◽  
Yohei Naito ◽  
...  
Keyword(s):  
Bone Loss ◽  
Messenger Rna ◽  
Cytotoxic T Lymphocyte ◽  
Mechanical Hyperalgesia ◽  
Micro Computed Tomography ◽  
Inhibitory Effects ◽  
Hind Limbs ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

This study aimed to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effects of cytotoxic T lymphocyte-associated antigen-4Ig (CTLA-4Ig) administration in ovariectomized (OVX) mice. Eight-week-old female ddY mice were assigned to three groups: sham-operated mice (SHAM) treated with vehicle, OVX mice treated with vehicle (OVX), and OVX mice treated with CTLA-4Ig (CTLA-4Ig). Vehicle or CTLA-4Ig was injected intraperitoneally, starting immediately after surgery. After 4 weeks of treatment, mechanical sensitivity was examined, and the bilateral hind limbs were removed and evaluated by micro-computed tomography, immunohistochemical analyses, and messenger RNA expression analysis. Ovariectomy induced bone loss and mechanical hyperalgesia in the hindlimbs. CTLA-4Ig treatment prevented bone loss in the hindlimbs compared to vehicle administration in the OVX group. Moreover, mechanical hyperalgesia was significantly decreased in the CTLA-4Ig treatment group in comparison to the OVX group. The expression levels of tumor necrosis factor-α (TNF-α) and sclerostin (SOST), as well as the number of osteoclasts, were increased, and the expression level of Wnt-10b was decreased in the OVX group compared with the SHAM group, whereas these parameters were improved in the CTLA-4Ig group compared with the OVX group. The novelty of this research is that CTLA-4Ig administration prevented bone loss and mechanical hyperalgesia induced by ovariectomy in the hindlimbs.

scholarly journals A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ying Liu ◽  
Wenjie Liu ◽  
Ziqiang Yu ◽  
Yan Zhang ◽  
Yinghua Li ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoporosis Treatment ◽  
Inhibitory Effect ◽  
Specific Gene ◽  
Actin Ring ◽  
Treatment Target ◽  
Significant Inhibitory Effect ◽  
Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

scholarly journals The Role of Alcohol, LPS Toxicity, and ALDH2 in Dental Bony Defects

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 651
Author(s):  
Hsiao-Cheng Tsai ◽  
Che-Hong Chen ◽  
Daria Mochly-Rosen ◽  
Yi-Chen Ethan Li ◽  
Min-Huey Chen
Keyword(s):  
Bone Loss ◽  
Bacterial Infection ◽  
Bone Regeneration ◽  
Alcohol Drinking ◽  
Bacterial Species ◽  
Dominant Negative ◽  
Enzyme Inactivation ◽  
Wild Type ◽  
Micro Computed Tomography ◽  
Dominant Negative Mutation

It is estimated that 560 million people carry an East Asian-specific ALDH2*2 dominant-negative mutation which leads to enzyme inactivation. This common ALDH2 polymorphism has a significant association with osteoporosis. We hypothesized that the ALDH2*2 mutation in conjunction with periodontal Porphyromonas gingivalis bacterial infection and alcohol drinking had an inhibitory effect on osteoblasts and bone regeneration. We examined the prospective association of ALDH2 activity with the proliferation and mineralization potential of human osteoblasts in vitro. The ALDH2 knockdown experiments showed that the ALDH2 knockdown osteoblasts lost their proliferation and mineralization capability. To mimic dental bacterial infection, we compared the dental bony defects in wild-type mice and ALDH2*2 knockin mice after injection with purified lipopolysaccharides (LPS), derived from P. gingivalis which is a bacterial species known to cause periodontitis. Micro-computed tomography (micro-CT) scan results indicated that bone regeneration was significantly affected in the ALDH2*2 knockin mice with about 20% more dental bony defects after LPS injection than the wild-type mice. Moreover, the ALDH2*2 knockin mutant mice had decreased osteoblast growth and more dental bone loss in the upper left jaw region after LPS injection. In conclusion, these results indicated that the ALDH2*2 mutation with alcohol drinking and chronic exposure to dental bacterial-derived toxin increased the risk of dental bone loss.

scholarly journals Inhibitory Effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside on RANKL-Induced Osteoclast Differentiation and ROS Generation in Macrophages

2020 ◽  
Vol 22 (1) ◽  
pp. 222
Author(s):  
Eun-Nam Kim ◽  
Ga-Ram Kim ◽  
Jae Sik Yu ◽  
Ki Hyun Kim ◽  
Gil-Saeng Jeong
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Disease ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Bone Diseases ◽  
Ros Generation ◽  
Bone Homeostasis ◽  
Disease Treatment ◽  
And Migration

In bone homeostasis, bone loss due to excessive osteoclasts and inflammation or osteolysis in the bone formation process cause bone diseases such as osteoporosis. Suppressing the accompanying oxidative stress such as ROS in this process is an important treatment strategy for bone disease. Therefore, in this study, the effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (BAG), an arylbutanoid glycoside isolated from Betula platyphylla var. japonica was investigated in RANKL-induced RAW264.7 cells and LPS-stimulated MC3E3-T1 cells. BAG inhibited the activity of TRAP, an important marker of osteoclast differentiation and F-actin ring formation, which has osteospecific structure. In addition, the protein and gene levels were suppressed of integrin β3 and CCL4, which play an important role in the osteoclast-induced bone resorption and migration of osteoclasts, and inhibited the production of ROS and restored the expression of antioxidant enzymes such as SOD and CAT lost by RANKL. The inhibitory effect of BAG on osteoclast differentiation and ROS production appears to be due to the inhibition of MAPKs phosphorylation and NF-κβ translocation, which play a major role in osteoclast differentiation. In addition, BAG inhibited ROS generated by LPS and effectively restores the mineralization of lost osteoblasts, thereby showing the effect of bone formation in the inflammatory situation accompanying bone loss by excessive osteoclasts, suggesting its potential as a new natural product-derived bone disease treatment.

Osteopontin is associated with nuclear factor κB gene expression during tail-suspension-induced bone loss

2006 ◽  
Vol 312 (16) ◽  
pp. 3075-3083 ◽  
Author(s):  
Muneaki Ishijima ◽  
Yoichi Ezura ◽  
Kunikazu Tsuji ◽  
Susan R. Rittling ◽  
Hisashi Kurosawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Loss ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Tail Suspension

scholarly journals Octanoic acid a major component of widely consumed medium-chain triglyceride ketogenic diet is detrimental to bone

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shreshta Jain ◽  
Reena Rai ◽  
Divya Singh ◽  
Divya Vohora
Keyword(s):  
Bone Loss ◽  
Ketogenic Diet ◽  
Octanoic Acid ◽  
Bone Microarchitecture ◽  
Medium Chain Triglyceride ◽  
Decanoic Acid ◽  
Clinical Findings ◽  
Micro Computed Tomography ◽  
Negative Effects ◽  
Treatment Groups

AbstractOctanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing medium chained triglycerides (MCT) along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. However, recent clinical findings have reported a critical disadvantage with the long-term consumption of ketogenic diet i.e. bone loss. The following study was employed to investigate whether the two major components of MCT diet also possess bone loss potential as observed with classical ketogenic diet. Swiss albino mice aged between 10 and 12 weeks, were divided into 3 treatment groups that were administered with oral suspensions of octanoic acid, decanoic acid and a combination of both for 4 weeks. Bone specific markers, microarchitectural parameters, using micro computed tomography, and biomechanical strength were analyzed. Remarkably deleterious alterations in the trabecular bone microarchitecture, and on bone markers were observed in the octanoic acid treated groups. Our results suggest significant negative effects on bone health by octanoic acid. These findings require further investigation and validation in order to provide significant clinically relevant data to possibly modify dietary composition of the MCT ketogenic diet.

scholarly journals Cyclic GMP regulates activation of phosphoinositidase C by bradykinin in sensory neurons

1996 ◽  
Vol 316 (2) ◽  
pp. 539-544 ◽  
Author(s):  
Justine S. HARVEY ◽  
Gillian M. BURGESS
Keyword(s):  
Cyclic Gmp ◽  
Inhibitory Effect ◽  
Neonatal Rat ◽  
Drg Neurons ◽  
Rapid Phase ◽  
Surface Receptors ◽  
Similar Inhibitory Effect ◽  
Key Factor ◽  
The Right ◽  
Oxide Synthase

Prior exposure of cultured neonatal rat dorsal root ganglion (DRG) neurons to bradykinin resulted in marked attenuation of bradykinin-induced activation of phosphoinositidase C (PIC). The (logconcentration)–response curve for bradykinin-induced [3H]inositol trisphosphate ([3H]IP3) formation was shifted to the right and the maximum response was reduced. Bradykinin increases cyclic GMP (cGMP) in DRG neurons [Burgess, Mullaney, McNeill, Coote, Minhas and Wood (1989) J. Neurochem. 53, 1212–1218] and treatment of the neurons with dibutyryl cGMP (dbcGMP) had a similar, inhibitory, effect on bradykinin-induced [3H]IP3 formation. NG-Nitro-L-arginine (LNNA) blocked bradykinin-induced formation of cGMP. It prevented the functional uncoupling induced by pretreatment with bradykinin, but not the inhibitory effect of dbcGMP on [3H]IP3 formation. The ability of LNNA to prevent desensitization was reversed by excess L-arginine, indicating that its actions were mediated through inhibition of nitric oxide synthase. In addition to functional desensitization, exposure to bradykinin reduced the number of cell-surface receptors detected with [3H]bradykinin, without affecting its KD value for the remaining sites. In contrast to bradykinin, pretreatment with dbcGMP had no effect on either the KD or Bmax for [3H]bradykinin binding. This implies that the inhibitory effect of dbcGMP was downstream from the binding of bradykinin to its receptor and upstream of IP3 formation. The lack of effect of dbcGMP on [3H]bradykinin binding suggests that the decrease in receptor number induced by bradykinin was mediated by a different mechanism and was not a key factor in the rapid phase of desensitization in these cells.

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