scholarly journals Crif1 Promotes Osteoporosis in Mice after Radiation

2019 ◽  
Author(s):  
Lixin Xiang ◽  
Li Chen ◽  
Yang Xiang ◽  
Fengjie Li ◽  
Xiaomei Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Loss ◽  
Bone Marrow Cells ◽  
Current Knowledge ◽  
Osteoclast Differentiation ◽  
Protein Docking ◽  
Rankl Expression ◽  
Marrow Cells

AbstractRadiation induces rapid bone loss and enhances bone resorption and RANKL expression. RANKL provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood. Here, we show that Crif1 expression increases in bone marrow cells after radiation. Conditional Crif1 deletion in bone marrow cells causes decreases in RANKL expression and the RANKL/OPG ratio, and relieves bone loss after radiation in mice. We further demonstrated in vitro that Crif1 promotes RANKL secretion via the cAMP/PKA pathway. Moreover, protein-protein docking screening identified five compounds as Crif1 inhibitors; these compounds dramatically suppressed RANKL secretion and CREB phosphorylation when cells were exposed to forskolin. This study enriches current knowledge of the pathogenesis of osteoporosis and provides insights into potential therapeutic strategies for osteoporosis treatment.

Thalidomide Derivative CC-4047 Inhibits Osteoclast Formation by down Regulation of PU.1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 629-629 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Gulsum Anderson ◽  
Noriyoshi Kurihara ◽  
Tadashi Honjo ◽  
Judith Anderson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Early Event ◽  
Down Regulation ◽  
Bone Marrow Cultures

Abstract CC-4047 (Actimid) is an immunomodulatory analog of thalidomide that has stronger anti-myeloma and anti-angiogenic activity than thalidomide, but its effects on human osteoclast lineage are unknown. Early osteoclast progenitors are of hematopoietic origin and progressively differentiate into mature bone resorbing multinucleated osteoclasts. We investigated the effects of CC-4047 and thalidomide on human osteoclastogenesis, using in vitro receptor activator of NFκ-B ligand/M-CSF stimulated culture system of bone marrow cells. Three weeks of treatment of primary bone marrow cultures with 100 μM CC-4047 decreased osteoclast formation accompanied by complete inhibition of bone resorption. Interestingly, osteoclast formation was also inhibited when cultures were treated with CC-4047 only for the first week (90% inhibition). In contrast, inhibitory effect was greatly diminished when the drug was given for only the last week (25% inhibition), indicating that inhibition of osteoclast formation is an early event. The inhibitory effect of CC-4047 on osteoclastogenesis was not induced by cell death, but by a shift of lineage commitment to granulocyte-CFU at the expense of GM-CFU that are osteoclast progenitors. Further studies revealed that this shift is mediated through down regulation of the transcription factor PU.1, which is critical for early osteoclast formation. In contrast to CC-4047, thalidomide was a significantly less potent inhibitor of osteoclast formation and bone resorption. These results provide the first evidence that CC-4047 blocks osteoclast differentiation at the early phase of osteoclastogenesis. Therefore, CC-4047 might be a valuable drug targeting both the tumor and osteoclastic activity in patients with multiple myeloma and potentially other diseases associated with the development of osteolytic lesions.

FLT3 ligand can substitute for macrophage colony-stimulating factor in support of osteoclast differentiation and function

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2707-2713 ◽  
Author(s):  
Jeny Maree Lean ◽  
Karen Fuller ◽  
Timothy John Chambers
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Osteoclast Differentiation ◽  
Colony Stimulating Factor ◽  
Flt3 Ligand ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Marrow Cells

Abstract Although bone resorption and osteoclast numbers are reduced in osteopetrotic (op/op) mice, osteoclasts are nevertheless present and functional, despite the absence of macrophage colony-stimulating factor (M-CSF). This suggests that alternative factors can partly compensate for the crucial actions of M-CSF in osteoclast induction. It was found that when nonadherent bone marrow cells were incubated in RANKL with Flt3 ligand (FL) without exogenous M-CSF, tartrate-resistance acid phosphatase (TRAP)–positive cells were formed, and bone resorption occurred. Without FL, only macrophagelike TRAP-negative cells were present. Granulocyte-macrophage CSF, stem cell factor, interleukin-3, and vascular endothelial growth factor could not similarly replace the need for M-CSF. TRAP-positive cell induction in FL was not due to synergy with M-CSF produced by the bone marrow cells themselves because FL also enabled their formation from the hemopoietic cells of op/op mice, which lack any M-CSF. FL appeared to substitute for M-CSF by supporting the differentiation of adherent cells that express mRNA for RANK and responsiveness to RANKL. To determine whether FL can account for the compensation for M-CSF deficiency that occurs in vivo, FL signaling was blockaded in op/op mice by the injection of soluble recombinant Flt3. It was found that the soluble receptor induced a substantial decrease in osteoclast number, strongly suggesting that FL is responsible for the partial compensation for M-CSF deficiency that occurs in these mice.

scholarly journals Flemingia macrophyllaExtract Ameliorates Experimental Osteoporosis in Ovariectomized Rats

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Hui-Ya Ho ◽  
Jin-Bin Wu ◽  
Wen-Chuan Lin
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Marrow Cells ◽  
Serum Alkaline Phosphatase ◽  
Osteoclast Differentiation ◽  
Ethanolic Extract ◽  
Ovariectomized Rats ◽  
Native Plant ◽  
Experimental Osteoporosis

Flemingia macrophylla(Leguminosae), a native plant of Taiwan, is used as folk medicine. Anin vitrostudy showed that a 75% ethanolic extract ofF. macrophylla(FME) inhibited osteoclast differentiation of cultured rat bone marrow cells, and the active component, lespedezaflavanone A (LDF-A), was isolated. It was found that oral administration of FME for 13 weeks suppressed bone loss in ovariectomized rats, an experimental model of osteoporosis. In addition, FME decreased urinary deoxypyridinoline concentrations but did not inhibit serum alkaline phosphatase activities, indicating that it ameliorated bone loss via inhibition of bone resorption. These results suggest that FME may represent a useful remedy for the treatment of bone resorption diseases, such as osteoporosis. In addition, LDF-A could be used as a marker compound to control the quality of FME.

Trehalose suppresses osteoclast differentiation in ovariectomized mice: Correlation with decreased in vitro interleukin-6 production by bone marrow cells

2000 ◽  
Vol 20 (10) ◽  
pp. 1485-1491 ◽  
Author(s):  
Chiyo Yoshizane ◽  
Norie Arai ◽  
Chikako Arai ◽  
Mayuko Yamamoto ◽  
Yasushi Nishizaki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Interleukin 6 ◽  
Bone Marrow Cells ◽  
Osteoclast Differentiation ◽  
Ovariectomized Mice ◽  
Marrow Cells

scholarly journals Effects and Interaction of Icariin, Curculigoside, and Berberine in Er-Xian Decoction, a Traditional Chinese Medicinal Formula, on Osteoclastic Bone Resorption

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Liming Xue ◽  
Lei Jiao ◽  
Yin Wang ◽  
Yan Nie ◽  
Ting Han ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Cathepsin K ◽  
Osteoclastic Bone Resorption ◽  
Tartrate Resistant Acid Phosphatase ◽  
Inhibitory Effects ◽  
Dihydroxyvitamin D ◽  
Marrow Cells

Er-Xian decoction (EXD), a traditional Chinese medicine, has been reported to have a protective effect against bone loss in ovariectomized osteoporotic rats, and the inclusion of icariin (I), curculigoside (C), and berberine (B) in EXD displays inhibitory effects on osteoclastic bone resorption. In the present paper, we investigated the interaction and effects of I, C, B, and their combination on bone resorption activityin vitroon osteoclasts derived from rat bone marrow cells. ICB synergistically decreased the formation of bone resorption pits, the number of multinucleated osteoclasts, and the activity of tartrate-resistant acid phosphatase (TRAP) and showed antagonistic or additive effects on cathepsin K activity in the coculture system of osteoblasts and bone marrow cells in the presence of 1, 25-dihydroxyvitamin D3and dexamethasone. The combination of ICB also enhanced the inhibitory effects on the formation of F-actin ring, a cytoskeleton structure of osteoclasts induced from bone marrow cells with macrophage colony stimulation factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). In addition, ICB synergistically improved the ratio of protein expression of osteoprotegerin (OPG) and RANKL in osteoblasts and interfered with the mitogen-activated protein kinases (MAPKs) pathway in osteoclast. These results clearly show that I, C, B, and their combination in EXD exert effects of mutual reinforcement. However, IBC does not show an intensified adverse effect in the ovariectomized murine model, as revealed by change in body and uterine weight, confirming the safety of EXD. These observations are in agreement with the rationality of the formula used in this paper.

In Vitro Osteoclast Differentiation of Bone Marrow Cells on Hydroxyapatite/Collagen Self-Organized Bone-Like Nanocomposite Disk

2008 ◽  
Vol 396-398 ◽  
pp. 449-452 ◽  
Author(s):  
Masanori Kikuchi ◽  
Atsushi Irie
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Control Cell ◽  
Osteoclast Differentiation ◽  
Mouse Bone Marrow ◽  
Self Organized ◽  
Osteoclastic Differentiation ◽  
Cells Cultured ◽  
Marrow Cells

Osteoclast differentiation of bone marrow cells on hydroxyapatite/collagen self-organized bone-like nanocomposite (HAp/Col) disk in vitro was evaluated by coculture of mouse bone marrow cells with mouse osteoblasts with or without addition of osteoclastic inducers, 1,25-Dihydroxyvitamin D3 and 1 µM prostaglandin E2. Dentine slice and tissue culture polystyrene were used as controls. Good osteoclastic differentiation at day 7 were observed among the bone marrow cells cultured on the HAp /Col disk and controls with osteoclastic inducers. On the contrary, osteoclastic differentiation was observed only for marrow cells cultured on the HAp/Col disk. Nano- and micro- structures as well as chemical and mechanical properties have a potential to control cell differentiation.

scholarly journals Runx1-Mediated Regulation of Osteoclast Differentiation and Function

2014 ◽  
Vol 28 (4) ◽  
pp. 546-553 ◽  
Author(s):  
Do Y. Soung ◽  
Judith Kalinowski ◽  
Sanjeev K. Baniwal ◽  
Christian E. Jacome-Galarza ◽  
Baruch Frenkel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Mass ◽  
Bone Marrow Cells ◽  
Osteoclast Formation ◽  
Mrna Levels ◽  
Metabolic Bone Diseases ◽  
And Function ◽  
Marrow Cells

Abstract Excessive bone resorption is the cause of several metabolic bone diseases including osteoporosis. Thus, identifying factors that can inhibit osteoclast formation and/or activity may define new drug targets that can be used to develop novel therapies for these conditions. Emerging evidence demonstrates that the master regulator of hematopoiesis, Runx1, is expressed in preosteoclasts and may influence skeletal health. To examine the potential role of Runx1 in osteoclast formation and function, we deleted its expression in myeloid osteoclast precursors by crossing Runx1 floxed mice (Runx1F/F) with CD11b-Cre transgenic mice. Mice lacking Runx1 in preosteoclasts (CD11b-Cre;Runx1F/F) exhibited significant loss of femoral trabecular and cortical bone mass compared with that in Cre-negative mice. In addition, serum levels of collagen type 1 cross-linked C-telopeptide, a biomarker of osteoclast-mediated bone resorption, were significantly elevated in CD11b-Cre;Runx1F/F mice compared with those in Runx1F/F mice. Tartrate-resistant acid phosphatase–positive osteoclasts that differentiated from bone marrow cells of CD11b-Cre;Runx1F/F mice in vitro were larger, were found in greater numbers, and had increased bone resorbing activity than similarly cultured cells from Runx1F/F mice. CD11b-Cre;Runx1F/F bone marrow cells that were differentiated into osteoclasts in vitro also had elevated mRNA levels of osteoclast-related genes including vacuolar ATPase D2, cathepsin K, matrix metalloproteinase 9, calcitonin receptor, osteoclast-associated receptor, nuclear factor of activated T cells cytoplasmic 1, and cFos. These data indicate that Runx1 expression in preosteoclasts negatively regulates osteoclast formation and activity and contributes to overall bone mass.

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