Chemokine and chemokine receptor expression during colony stimulating factor-1–induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1γ) in osteoclastogenesis in vivo and in vitro

Yang, Meilheng; Mailhot, Geneviève; MacKay, Carole A.; Mason‐Savas, April; Aubin, Justin; Odgren, Paul R.

doi:10.1182/blood-2005-08-3365

Cited by 76 publications

(66 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(31)(32)(33) In in vitro OC cultures and animal models, such as tl/tl rats and op/op mice, an absence of signaling through c-fms results in a severe depletion of OCs and OC precursors. (10)(11)(12)30) c-fms signaling also functions by inducing the expression of a number of OC-associated genes, including RANK. (34) c-Src is also known to play an important role in OC activity in vivo, as demonstrated by c-Src -/-mice, which are severely osteopetrotic owing to an absence of OC activity.…”

Section: Discussionmentioning

confidence: 99%

“…(9)(10)(11)(12) There is growing in vitro evidence that inhibition of c-fms by dasatinib can inhibit OC formation and activity. Treatment with dasatinib at clinically relevant concentrations inhibits the formation and activity of tartrate-resistant acid phosphatase (TRACP)-positive OCs from human peripheral blood mononuclear cells and primary mouse bone marrow cells in vitro.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 mg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib-or ZOL-treated animals relative to controls. However, micro-computed tomographic (mCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling. ß

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Vandyke

Dewar

Diamond

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…These probes were hybridized to the Mouse MG-U74Av2 chip from Affymetrix according to the manufacturer's instruction, at the Harvard Bauer Center for Genomics Research (Cambridge, MA). Microarray analysis of CSF-1-induced gene expression changes in tl/tl rats during time course of CSF-1 injections was described in detail in Yang et al 15 . In brief, homozygous mutant animals were IP injected daily with 10 6 Units of recombinant human CSF-1 (Chiron).…”

Section: Microarray Hybridizationmentioning

confidence: 99%

“…We next investigated expression in bone during rapid osteoclast differentiation in vivo induced by colony-stimulating factor 1 (CSF-1) in Csf-1-null toothless (tl/tl) rats 15 . In CSF-1-treated tl rats ( Figure 3B) nha-oc/NHA2 increased after 2 days compared with untreated controls.…”

Section: Nha-oc/nha2 Is Expressed In Differentiated Osteoclastsmentioning

confidence: 99%

NHA-oc/NHA2: A mitochondrial cation–proton antiporter selectively expressed in osteoclasts

Battaglino¹,

Pham²,

Morse

et al. 2008

Bone

View full text Add to dashboard Cite

Bone resorption is regulated by a complex system of hormones and cytokines that cause osteoblasts/stromal cells and lymphocytes to produce factors including RANKL, that ultimately result in the differentiation and activation of osteoclasts, the bone resorbing cells.We used a microarray approach to identify genes upregulated in RANKL-stimulated osteoclastprecursor cells. Osteoclast expression was confirmed by multiple tissue Northern and in situ hybridization analysis. Gene function studies were carried out by siRNA analysis.We identified a novel gene, which we termed nha-oc/NHA2, which is strongly upregulated during RANKL-induced osteoclast differentiation in vitro and in vivo. nha-oc/NHA2 encodes a novel cation/proton antiporter (CPA), and is the mouse orthologue of a human gene identified in a database search: HsNHA2. nha-oc/NHA2 is selectively expressed in osteoclasts. NHA-oc/NHA2 protein localizes to the mitochondria, where it mediates Na + -dependent changes in mitochondrial pH and Na + Acetate induced-mitochondrial passive swelling. RNA silencing of nha-oc/nha2 reduces osteoclast differentiation and resorption, suggesting a role for NHA-oc/NHA2 in these processes.nha-oc/NHA2 therefore is a novel member of the CPA family, and is the first mitochondrial NHA characterized to date. nha-oc/NHA2 is also unique in that it is the first eukaryotic and tissue specific CPA2 characterized to date. NHA-oc/NHA2 displays the expected activities of a bona fide CPA and plays a key role(s) in normal osteoclast differentiation and function.

show abstract

“…The M-CSF receptor, c-Fms, is highly expressed on mature osteoclasts (28), and interaction of M-CSF with c-Fms promotes actin reorganization and cell spreading. Src is likely to be required in this pathway because the ability of M-CSF to modulate cytoskeleton reorganization is not observed in osteoclasts derived from src Ϫ/Ϫ mice, and M-CSF induces Src-dependent tyrosine phosphorylation in osteoclasts (29,30).…”

Section: -Aag Prolongs M-csf-induced Src Kinase Activation and Potementioning

confidence: 99%

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Srcdependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.cancer ͉ geldanamycin ͉ heat shock protein 90 ͉ osteoclastogenesis

show abstract

Chemokine and chemokine receptor expression during colony stimulating factor-1–induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1γ) in osteoclastogenesis in vivo and in vitro

Cited by 76 publications

References 40 publications

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

NHA-oc/NHA2: A mitochondrial cation–proton antiporter selectively expressed in osteoclasts

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Contact Info

Product

Resources

About