Dietary compound gossypetin inhibits bone resorption through down-regulating lysosomal cathepsin K activity and autophagy-related protein induction in actin ring-bearing osteoclasts

2016 ◽  
Vol 24 ◽  
pp. 390-402 ◽  
Author(s):  
Lucia Dwi Antika ◽  
Yun-Ho Kim ◽  
Min-Kyung Kang ◽  
Sin-Hye Park ◽  
Eun-Jung Lee ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Cathepsin K ◽  
Related Protein ◽  
Actin Ring ◽  
K Activity

scholarly journals Cathepsin K Activity-dependent Regulation of Osteoclast Actin Ring Formation and Bone Resorption

2008 ◽  
Vol 284 (4) ◽  
pp. 2584-2592 ◽  
Author(s):  
Susan R. Wilson ◽  
Christoph Peters ◽  
Paul Saftig ◽  
Dieter Brömme
Keyword(s):  
Bone Resorption ◽  
Cathepsin K ◽  
Ring Formation ◽  
Actin Ring ◽  
Activity Dependent ◽  
K Activity

scholarly journals Osteoclasts’ Ability to Generate Trenches Rather Than Pits Depends on High Levels of Active Cathepsin K and Efficient Clearance of Resorption Products

2020 ◽  
Vol 21 (16) ◽  
pp. 5924
Author(s):  
Xenia G. Borggaard ◽  
Dinisha C. Pirapaharan ◽  
Jean-Marie Delaissé ◽  
Kent Søe
Keyword(s):  
Bone Resorption ◽  
Bone Erosion ◽  
Cathepsin K ◽  
Time Lapse ◽  
Bone Surface ◽  
Cycle Model ◽  
Actin Ring ◽  
Mode 2 ◽  
Clinical Interest ◽  
Effective Seal

Until recently, it was well-accepted that osteoclasts resorb bone according to the resorption cycle model. This model is based on the assumption that osteoclasts are immobile during bone erosion, allowing the actin ring to be firmly attached and thereby provide an effective seal encircling the resorptive compartment. However, through time-lapse, it was recently documented that osteoclasts making elongated resorption cavities and trenches move across the bone surface while efficiently resorbing bone. However, it was also shown that osteoclasts making rounded cavities and pits indeed resorb bone while they are immobile. Only little is known about what distinguishes these two different resorption modes. This is of both basic and clinical interest because these resorption modes are differently sensitive to drugs and are affected by the gender as well as age of the donor. In the present manuscript we show that: 1. levels of active cathepsin K determine the switch from pit to trench mode; 2. pit and trench mode depend on clathrin-mediated endocytosis; and 3. a mechanism integrating release of resorption products and membrane/integrin recycling is required for prolongation of trench mode. Our study therefore contributes to an improved understanding of the molecular and cellular determinants for the two osteoclastic bone resorption modes.

Localization of Rat Cathepsin K in Osteoclasts and Resorption Pits: Inhibition of Bone Resorption and Cathepsin K-Activity by Peptidyl Vinyl Sulfones

1999 ◽  
Vol 380 (6) ◽  
Author(s):  
L. Xia ◽  
J. Kilb ◽  
H. Wex ◽  
Z. Li ◽  
A. Lipyansky ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Cathepsin L ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Cathepsin K ◽  
Selective Inhibition ◽  
Specific Substrate ◽  
Dependent Manner ◽  
Protease Inhibition ◽  
K Activity

AbstractWe have localized cathepsin K in rat osteoclasts and within exposed resorption pits by immuno-fluorescence microscopy. Intracellular staining using an antibody raised against recombinant mouse cathepsin K was vesicular and uniformly distributed throughout the cell. Confocal microscopy analysis did not reveal an accumulation of cathepsin K containing vesicles opposing the ruffled border and the resorption lacuna. Exposed resorption pits exhibited a uniform distribution of cathepsin K, and no differences were observed between the edges and the centers of the pits. The immunostaining of resorption pits with anti-cathepsin K antibodies demonstrates that the protease is secreted into the sub-osteoclastic compartment.Cathepsin K-specific inhibition using peptidyl vinyl sulfones as selective cysteine protease inactivators reduced bone resorption by 80% in a dose-dependent manner at sub-micromolar concentrations. No reduction of bone resorption was observed at those low concentrations using a potent cathepsin L, S, B-specific inhibitor. That the inhibition of bone resorption can be attributed to cathepsin K-like protease inhibition was corroborated by the selective inhibition of the osteoclastic Z-Gly-Pro-Arg-MβNA hydrolyzing activity by the cathepsin K, L, S, B-inhibitor, but not by the cathepsin L, B, and S inhibitor. Z-Gly-Pro-Arg-MβNA is efficiently hydrolyzed by cathepsin K but only poorly by cathepsins L, S, and B. On the contrary, the intracellular hydrolysis of the cathepsin B-specific substrate, Z-Arg-Arg-MβNA, was prevented by both types of inhibitors.The identification of cathepsin K in resorption pits and the inhibition of bone resorption and intracellular cathepsin K activity by selective vinyl sulfone inhibitors indicate the critical role of the protease in osteoclastic bone resorption.

scholarly journals Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 619
Author(s):  
Hyun-Jung Park ◽  
Malihatosadat Gholam-Zadeh ◽  
Sun-Young Yoon ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Ring Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Actin Ring ◽  
Collagen Crosslinks ◽  
Trap Staining ◽  
Src Activation

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p–Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

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

Inhibition ofUlmus davidiana Planch (Ulmaceae) on bone resorption mediated by processing of Cathepsin K in cultured mouse osteoclasts

2008 ◽  
Vol 22 (4) ◽  
pp. 511-517 ◽  
Author(s):  
Kyung-Woon Kim ◽  
Jun-Sung Park ◽  
Kap-Sung Kim ◽  
Un-Ho Jin ◽  
June-Ki Kim ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Cathepsin K

Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio

Bone ◽  
2005 ◽  
Vol 36 (1) ◽  
pp. 159-172 ◽  
Author(s):  
Riku Kiviranta ◽  
Jukka Morko ◽  
Sari L. Alatalo ◽  
Roisin NicAmhlaoibh ◽  
Juha Risteli ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Cathepsin K ◽  
Deficient Mice

Effect of Icariin on Osteoclasts and Its Mechanism

2020 ◽  
Vol 10 (12) ◽  
pp. 1807-1812
Author(s):  
Xiaoxiao Wu ◽  
Xi Fu ◽  
Xiabing Qin
Keyword(s):  
Transcription Factors ◽  
Bone Resorption ◽  
Bone Loss ◽  
Mapk Pathway ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Mapk Signaling ◽  
Therapeutic Drug ◽  
Actin Ring ◽  
B Subunit

Background: The paper aimed to elucidate the molecular mechanism of Icariin regulating RANKLinduced osteoclast-ogenesis and bone resorption, and to investigate whether Icariin could be a potential therapeutic drug for diseases of bone loss related to osteoclast. Material and methods: Osteoclasts were cultured. MTT to determine cell viability. Von Kossa to determine the effect of Icariin on bone resorption. F-actin ring staining to measure the expressions of various proteins, and WB method was used to measure the expression of p-65. Results: MTT showed that Icariin is not toxic to osteoclasts. The bone resorption result showed that RANKL-mediated osteoclast bone resorption was reduced in the early stage, and the higher the intervention concentration, the smaller the bone resorption area. F-actin ring staining indicated that it is possible to reduce the differentiation and bone resorption capacity of osteoclasts by hindering the formation of F-actin ring in the early stage, and in a concentration-dependentmanner. Significantly reduced the expressions of key transcription factors-NFATc1 and c-Fos. It significantly inhibited the phosphorylation and nucleation of NF-κB subunit p65 induced by RANKL, and significantly inhibited the phosphorylation of ERK and p38 proteins in the MAPK pathway activated by RANKL. Conclusion: Icariin can effectively inhibit osteoclast differentiation, F-actin ring formation, and bone resorption. By inhibiting the key transcription factors NFATc1 and c-Fos to down-regulate related expressions, thereby impeding osteoclast differentiation, Icariin may regulate key transcription factors NFATc1 and c-Fos through NF-κB and MAPK signaling pathways. Studies have suggested that Icariin could be a potential treatment for diseases of bone loss related to osteoclasts.

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