scholarly journals (23S)-25-Dehydro-1α-Hydroxyvitamin D3-26,23-Lactone, a Vitamin D Receptor Antagonist that Inhibits Osteoclast Formation and Bone Resorption in Bone Marrow Cultures from Patients with Paget’s Disease

Endocrinology ◽  
2005 ◽  
Vol 146 (4) ◽  
pp. 2023-2030 ◽  
Author(s):  
Seiichi Ishizuka ◽  
Noriyoshi Kurihara ◽  
Sakamuri V. Reddy ◽  
Jillian Cornish ◽  
Tim Cundy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vitamin D ◽  
Bone Resorption ◽  
Receptor Antagonist ◽  
Vitamin D Receptor ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Osteoclast Formation ◽  
Bone Marrow Cultures ◽  
Marrow Cultures

Inhibition of intravacuolar acidification by antisense RNA decreases osteoclast differentiation and bone resorption in vitro

1999 ◽  
Vol 112 (21) ◽  
pp. 3657-3666 ◽  
Author(s):  
T. Laitala-Leinonen ◽  
C. Lowik ◽  
S. Papapoulos ◽  
H.K. Vaananen
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Antisense Rna ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Gm Csf ◽  
Monocytes And Macrophages ◽  
Marrow Cultures ◽  
Rat Bone

The role of proton transport and production in osteoclast differentiation was studied in vitro by inhibiting the transcription/translation of carbonic anhydrase II (CA II) and vacuolar H(+)-ATPase (V-ATPase) by antisense RNA molecules. Antisense RNAs targeted against CA II, or the 16 kDa or 60 kDa subunit of V-ATPase were used to block the expression of the specific proteins. A significant decrease in bone resorption rate and TRAP-positive osteoclast number was seen in rat bone marrow cultures and fetal mouse metacarpal cultures after antisense treatment. Intravacuolar acidification in rat bone marrow cells was also significantly decreased after antisense treatment. The CA II antisense RNA increased the number of TRAP-positive mononuclear cells, suggesting inhibition of osteoclast precursor fusion. Antisense molecules decreased the number of monocytes and macrophages, but increased the number of granulocytes in marrow cultures. GM-CSF, IL-3 and IL-6 were used to stimulate haematopoietic stem cell differentiation. The 16 kDa V-ATPase antisense RNA abolished the stimulatory effect of GM-CSF, IL-3 and IL-6 on TRAP-positive osteoclast formation, but did not affect the formation of monocytes and macrophages after IL-3 treatment, or the formation of granulocytes after IL-6 treatment. These results suggest that CA II and V-ATPase are needed, not only for the actual resorption, but also for osteoclast formation in vitro.

scholarly journals The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures.

1996 ◽  
Vol 183 (6) ◽  
pp. 2581-2591 ◽  
Author(s):  
E Romas ◽  
N Udagawa ◽  
H Zhou ◽  
T Tamura ◽  
M Saito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Osteoclast Formation ◽  
Pcr Analysis ◽  
Dihydroxyvitamin D3 ◽  
Bone Marrow Cultures ◽  
Primary Osteoblasts ◽  
Marrow Cultures

Interleukin (IL)-11 is a multifunctional cytokine whose role in osteoclast development has not been fully elucidated. We examined IL-11 production by primary osteoblasts and the effects of rat monoclonal anti-mouse glycoprotein 130 (gp130) antibody on osteoclast formation, using a coculture of mouse osteoblasts and bone marrow cells. IL-1, TNF alpha, PGE2, parathyroid hormone (PTH) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) similarly induced production of IL-11 by osteoblasts, but IL-6, IL-4, and TGF beta did not. Primary osteoblasts constitutively expressed mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Osteotropic factors did not modulate IL-11R alpha mRNA at 24 h, but steady-state gp130 mRNA expression in osteoblasts was upregulated by 1 alpha,25(OH)2D3, PTH, or IL-1. In cocultures, the formation of multinucleated osteoclast-like cells (OCLs) in response to IL-11, or IL-6 together with its soluble IL-6 receptor was dose-dependently inhibited by rat monoclonal anti-mouse gp130 antibody. Furthermore, adding anti-gp130 antibody abolished OCL formation induced by IL-1, and partially inhibited OCL formation induced by PGE2, PTH, or 1 alpha,25(OH)2D3. During osteoclast formation in marrow cultures, a sequential relationship existed between the expression of calcitonin receptor mRNA and IL-11R alpha mRNA. Osteoblasts as well as OCLs expressed transcripts for IL-11R alpha, as indicated by RT-PCR analysis and in situ hybridization. These results suggest a central role of gp130-coupled cytokines, especially IL-11, in osteoclast development. Since osteoblasts and mature osteoclasts expressed IL-11R alpha mRNA, both bone-forming and bone-resorbing cells are potential targets of IL-11.

scholarly journals Impaired Osteoclast Formation in Bone Marrow Cultures of Fgf2 Null Mice in Response to Parathyroid Hormone

2003 ◽  
Vol 278 (23) ◽  
pp. 21258-21266 ◽  
Author(s):  
Yosuke Okada ◽  
Aldemar Montero ◽  
Xuxia Zhang ◽  
Takanori Sobue ◽  
Joseph Lorenzo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Parathyroid Hormone ◽  
Osteoclast Formation ◽  
Bone Marrow Cultures ◽  
Marrow Cultures

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.

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