Inhibition of miR-29 activity in the myeloid lineage increases response to calcitonin and trabecular bone volume in mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Bongjin Shin ◽  
Henry C Hrdlicka ◽  
Anne M Delany ◽  
Sun-Kyeong Lee
Keyword(s):  
Bone Resorption ◽  
Cortical Bone ◽  
Cathepsin K ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Bone Volume ◽  
Bone Homeostasis ◽  
Myeloid Lineage ◽  
Camp Levels

Abstract The miR-29-3p family (miR-29a, miR-29b, miR-29c) of microRNAs is increased during RANKL-induced osteoclastogenesis. In vivo, activation of a miR-29-3p tough decoy inhibitor (TuD) in LysM-cre expressing cells (myeloid lineage) resulted in mice displaying enhanced trabecular and cortical bone volume, due to decreased bone resorption. Calcitonin receptor (Calcr) is a miR-29 target that negatively regulates bone resorption. CALCR was significantly increased in RANKL-treated miR-29-decoy osteoclasts, and these cells were more responsive to the inhibitory effect of calcitonin on osteoclast formation. Further, cathepsin K (Ctsk), which is critical for resorption, was decreased in miR-29-decoy cells. CALCR is a Gs coupled receptor and its activation raises cAMP levels. In turn, cAMP suppresses cathepsin K, and cAMP levels were increased in miR-29-decoy cells. siRNA-mediated knock down of Calcr in miR-29 decoy osteoclasts allowed recovery of cathepsin K levels in these cells. Overall, using a novel knockin tough decoy mouse model, we identified a new role for miR-29-3p in bone homeostasis. In RANKL-driven osteoclastogenesis, as seen in normal bone remodeling, miR-29-3p promotes resorption. Consequently, inhibition of miR-29-3p activity in the myeloid lineage leads to increased trabecular and cortical bone. Further, this study documents an inter-relationship between CALCR and CTSK in osteoclastic bone resorption, which is modulated by miR-29-3p.

scholarly journals LY900009 Regulates RANKL-Induced Osteoclast Formation and LPS-Induced Bone Resorption

2020 ◽  
Author(s):  
Tao Huang ◽  
Congyun Zhao ◽  
Yi Zhao ◽  
Yuan Zhou ◽  
Lei Wang ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Dependent Manner ◽  
In Vivo Experiments ◽  
Secretase Inhibitor ◽  
Formation Number

Abstract To investigate the suppressive function of LY900009, a potent-secretase inhibitor, on RANKL-induced osteoclastogenesis. The cytotoxicity of LY900009 was evaluated. The suppressive effect and possible molecular mechanism of LY900009 on RANKL-induced osteoclastogenesis was evaluated both in vitro and in vivo. The IC50 of LY900009 was 2.93 mM. LY900009 treatment at different doses (100 nM, 200 nM, and 400 nM) effectively reduced osteoclast formation (number and arear) in a dose-dependent manner. The qPCR result shows that LY900009 attenuates RANKL-induced osteoclast formation and NFATc1 protein expression. The in vivo experiments demonstrated the inhibitory effect of LY900009 on LPS-induced bone resorption. LY900009 could potently inhibit osteoclastogenesis and bone resorption by down-regulating Notch/MAPK/Akt - mediated NFATc1 reduction in vitro. In accordance with the in vitro observations, we confirmed that LY900009 attenuated LPS-induced osteolysis in mice. In conclusion, our findings indicate that Notch was a potential therapeutic target which could be used for osteolytic diseases treatment.

scholarly journals Biological Effects of β-Glucans on Osteoclastogenesis

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1982
Author(s):  
Wataru Ariyoshi ◽  
Shiika Hara ◽  
Ayaka Koga ◽  
Yoshie Nagai-Yoshioka ◽  
Ryota Yamasaki
Keyword(s):  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Biological Effects ◽  
Osteoclast Differentiation ◽  
Treatment Strategies ◽  
Alcaligenes Faecalis ◽  
Osteoclast Formation ◽  
Osteoclast Precursors

Although the anti-tumor and anti-infective properties of β-glucans have been well-discussed, their role in bone metabolism has not been reviewed so far. This review discusses the biological effects of β-glucans on bone metabolisms, especially on bone-resorbing osteoclasts, which are differentiated from hematopoietic precursors. Multiple immunoreceptors that can recognize β-glucans were reported to be expressed in osteoclast precursors. Coordinated co-stimulatory signals mediated by these immunoreceptors are important for the regulation of osteoclastogenesis and bone remodeling. Curdlan from the bacterium Alcaligenes faecalis negatively regulates osteoclast differentiation in vitro by affecting both the osteoclast precursors and osteoclast-supporting cells. We also showed that laminarin, lichenan, and glucan from baker’s yeast, as well as β-1,3-glucan from Euglema gracilisas, inhibit the osteoclast formation in bone marrow cells. Consistent with these findings, systemic and local administration of β-glucan derived from Aureobasidium pullulans and Saccharomyces cerevisiae suppressed bone resorption in vivo. However, zymosan derived from S. cerevisiae stimulated the bone resorption activity and is widely used to induce arthritis in animal models. Additional research concerning the relationship between the molecular structure of β-glucan and its effect on osteoclastic bone resorption will be beneficial for the development of novel treatment strategies for bone-related diseases.

Inhibitory effect of ipriflavone on osteoclast-mediated bone resorption and new osteoclast formation in long-term cultures of mouse unfractionated bone cells

1993 ◽  
Vol 53 (3) ◽  
pp. 206-209 ◽  
Author(s):  
Kohei Notoya ◽  
Keiji Yoshida ◽  
Shigehisa Taketomi ◽  
Iwao Yamazaki ◽  
Masayoshi Kumegawa
Keyword(s):  
Bone Resorption ◽  
Bone Cells ◽  
Inhibitory Effect ◽  
Osteoclast Formation

A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys

Bone ◽  
2007 ◽  
Vol 40 (1) ◽  
pp. 122-131 ◽  
Author(s):  
S. Kumar ◽  
L. Dare ◽  
J.A. Vasko-Moser ◽  
I.E. James ◽  
S.M. Blake ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Turnover ◽  
Potent Inhibitor ◽  
Cathepsin K

Role Of Cyclic Amp In The Inhibition Of Human Platelet Functions By Quercetin, A Flav0N0Id That Potentiates PGI2 Effect

1981 ◽  
Author(s):  
J P Cazenave ◽  
A Beretz ◽  
A Stierlé ◽  
R Anton
Keyword(s):  
Maximum Level ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Pde Inhibitors ◽  
Pde Inhibition ◽  
Induced Aggregation ◽  
Camp Levels ◽  
Dose Dependent

Injury to the endothelium (END) and subsequent platelet (PLAT)interactions with the subEND are important steps in thrombosis and atherosclerosis. Thus,drugs that protect the END from injury and also inhibit PLAT function are of interest. It has been shown that some flavonoids(FLA), a group of compounds found in plants, prevent END desquamation in vivo, inhibit cyclic nucleotide phosphodiesterases(PDE)and inhibit PLAT function. We have studied the structure-activity relationships of 13 purified FLA on aggregation and secretion of 14c-5HT of prelabeled washed human PLAT induced by ADP, collagen(COLL) and thrombin(THR). All the FLA were inhibitors of the 3 agents tested. Quercetin(Q), was the second best after fisetin. It inhibited secretion and aggregation with I50 of 330µM against 0.1 U/ML.THR, 102µM against 5µM ADP and 40 µM against COLL. This inhibitory effect is in the range of that of other PDE inhibitors like dipyridamole or 3-isobutyl-l- methylxanthine. The aggregation induced by ADP, COLL and THR is at least mediated by 3 mechanisms that can be inhibited by increasing cAMP levels. We next investigated if Q, which is a PDE inhibitor of bovine aortic microsomes,raises PLAT cAMP levels. cAMP was measured by a protein-binding method. ADP- induced aggregation(5µM) was inhibited by PGI2 (0.1 and 0.5 nM) . Inhibition was further potentiated(l.7 and 3.3 times) by lOµM Q, which alone has no effect on aggregation. The basal level of cAMP(2.2 pmol/108PLAT) was not modified by Q (50 to 500µM). Using these concentrations of Q,the rise in cAMP caused by PGI2(0.1 and 0.5nM) was potentiated in a dose dependent manner. Q potentiated the effect of PGI2 on the maximum level of cAMP and retarded its breakdown. Thus Q and possibly other FLA could inhibit the interaction of PLAT with the components of the vessel wall by preventing END damage and by inhibiting PLAT function through a rise in cAMP secondary to PDE inhibition and potentiation of the effect of vascular PGI2 on PLAT adenylate cyclase.

scholarly journals Piceatannol attenuates RANKL-induced osteoclast differentiation and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promotes Caspase3-mediated apoptosis of mature osteoclasts

2019 ◽  
Vol 6 (6) ◽  
pp. 190360 ◽  
Author(s):  
Liuliu Yan ◽  
Lulu Lu ◽  
Fangbin Hu ◽  
Dattatrya Shetti ◽  
Kun Wei
Keyword(s):  
Bone Resorption ◽  
Osteoclast Differentiation ◽  
Giant Cells ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Signalling Pathways ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
And Function

Osteoclasts are multinuclear giant cells that have unique ability to degrade bone. The search for new medicines that modulate the formation and function of osteoclasts is a potential approach for treating osteoclast-related bone diseases. Piceatannol (PIC) is a natural organic polyphenolic stilbene compound found in diverse plants with a strong antioxidant and anti-inflammatory effect. However, the effect of PIC on bone health has not been scrutinized systematically. In this study, we used RAW264.7, an osteoclast lineage of cells of murine macrophages, to investigate the effects and the underlying mechanisms of PIC on osteoclasts. Here, we demonstrated that PIC treatment ranging from 0 to 40 µM strongly inhibited osteoclast formation and bone resorption in a dose-dependent manner. Furthermore, the inhibitory effect of PIC was accompanied by the decrease of osteoclast-specific genes. At the molecular level, PIC suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK1/2), NF-κB p65, IκBα and AKT. Besides, PIC promoted the apoptosis of mature osteoclasts by inducing caspase-3 expression. In conclusion, our results suggested that PIC inhibited RANKL-induced osteoclastogenesis and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promoted caspase3-mediated apoptosis of mature osteoclasts, which might contribute to the treatment of bone diseases characterized by excessive bone resorption.

scholarly journals Peptide Aldehyde Inhibitors of Cathepsin K Inhibit Bone Resorption Both In Vitro and In Vivo

1997 ◽  
Vol 12 (9) ◽  
pp. 1396-1406 ◽  
Author(s):  
Bartholomew J. Votta ◽  
Mark A. Levy ◽  
Alison Badger ◽  
Jeremy Bradbeer ◽  
Robert A. Dodds ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Cathepsin K ◽  
Inhibit Bone Resorption

scholarly journals Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

2018 ◽  
Vol 238 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Thomas Funck-Brentano ◽  
Karin H Nilsson ◽  
Robert Brommage ◽  
Petra Henning ◽  
Ulf H Lerner ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bending Test ◽  
Bone Homeostasis ◽  
Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

scholarly journals Inhibition of osteoclast differentiation and bone resorption by polyunsaturated fatty acids in RAW 264.7 murine macrophages

2012 ◽  
Vol 31 (1) ◽  
Author(s):  
J. C. Boeyens ◽  
W-H. Chua ◽  
M.C. Kruger ◽  
A.M. Joubert ◽  
M. Coetzee
Keyword(s):  
Fatty Acids ◽  
Bone Resorption ◽  
Polyunsaturated Fatty Acids ◽  
Cell Line ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Raw 264.7 ◽  
Murine Macrophages

This study investigated the effects of polyunsaturated fatty acids on osteoclast formation and bone resorption in RAW 264.7 murine pre-osteoclasts. Data obtained suggests an inhibitory effect of these compounds on osteoclastogenesis and bone resorption in the cell line tested.

Overexpression of Fam20C in osteoblast in vivo leads to increased cortical bone formation and osteoclastic bone resorption

Bone ◽  
2020 ◽  
Vol 138 ◽  
pp. 115414
Author(s):  
Katsutoshi Hirose ◽  
Takuya Ishimoto ◽  
Yu Usami ◽  
Sunao Sato ◽  
Kaori Oya ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Cortical Bone ◽  
Osteoclastic Bone Resorption
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