scholarly journals CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules

2008 ◽  
Vol 205 (10) ◽  
pp. 2381-2395 ◽  
Author(s):  
Shoham Shivtiel ◽  
Orit Kollet ◽  
Kfir Lapid ◽  
Amir Schajnovitz ◽  
Polina Goichberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nuclear Factor Κb ◽  
Hematopoietic Progenitors ◽  
Receptor Activator ◽  
Response To Stress ◽  
Stress Signals ◽  
Osteoclast Function ◽  
Metaphyseal Bone ◽  
Metalloproteinase 9 ◽  
Stimulating Factor

The CD45 phosphatase is uniquely expressed by all leukocytes, but its role in regulating hematopoietic progenitors is poorly understood. We show that enhanced CD45 expression on bone marrow (BM) leukocytes correlates with increased cell motility in response to stress signals. Moreover, immature CD45 knockout (KO) cells showed defective motility, including reduced homing (both steady state and in response to stromal-derived factor 1) and reduced granulocyte colony-stimulating factor mobilization. These defects were associated with increased cell adhesion mediated by reduced matrix metalloproteinase 9 secretion and imbalanced Src kinase activity. Poor mobilization of CD45KO progenitors by the receptor activator of nuclear factor κB ligand, and impaired modulation of the endosteal components osteopontin and stem cell factor, suggested defective osteoclast function. Indeed, CD45KO osteoclasts exhibited impaired bone remodeling and abnormal morphology, which we attributed to defective cell fusion and Src function. This led to irregular distribution of metaphyseal bone trabecules, a region enriched with stem cell niches. Consequently, CD45KO mice had less primitive cells in the BM and increased numbers of these cells in the spleen, yet with reduced homing and repopulation potential. Uncoupling environmental and intrinsic defects in chimeric mice, we demonstrated that CD45 regulates progenitor movement and retention by influencing both the hematopoietic and nonhematopoietic compartments.

scholarly journals Microphthalmia-associated Transcription Factor Interactions with 14-3-3 Modulate Differentiation of Committed Myeloid Precursors

2006 ◽  
Vol 17 (9) ◽  
pp. 3897-3906 ◽  
Author(s):  
Agnieszka Bronisz ◽  
Sudarshana M. Sharma ◽  
Rong Hu ◽  
Jakub Godlewski ◽  
Guri Tzivion ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Amino Acid Residues ◽  
Binding Partner ◽  
Kinase C ◽  
Receptor Activator ◽  
Factor Interactions ◽  
Stimulating Factor

The microphthalmia-associated transcription factor (MITF) is required for terminal osteoclast differentiation and is a target for signaling pathways engaged by colony stimulating factor (CSF)-1 and receptor-activator of nuclear factor-κB ligand (RANKL). Work presented here demonstrates that MITF can shuttle from cytoplasm to nucleus dependent upon RANKL/CSF-1 action. 14-3-3 was identified as a binding partner of MITF in osteoclast precursors, and overexpression of 14-3-3 in a transgenic model resulted in increased cytosolic localization of MITF and decreased expression of MITF target genes. MITF/14-3-3 interaction was phosphorylation dependent, and Ser173 residue, within the minimal interaction region of amino acid residues 141–191, was required. The Cdc25C-associated kinase (C-TAK)1 interacted with an overlapping region of MITF. C-TAK1 increased MITF/14-3-3 complex formation and thus promoted cytoplasmic localization of MITF. C-TAK1 interaction was disrupted by RANKL/CSF-1 treatment. The results indicate that 14-3-3 regulates MITF activity by promoting the cytosolic localization of MITF in the absence of signals required for osteoclast differentiation. This work identifies a mechanism that regulates MITF activity in monocytic precursors that are capable of undergoing different terminal differentiation programs, and it provides a mechanism that allows committed precursors to rapidly respond to signals in the bone microenvironment to promote specifically osteoclast differentiation.

scholarly journals Osteoclasts are important for bone angiogenesis

Blood ◽  
2010 ◽  
Vol 115 (1) ◽  
pp. 140-149 ◽  
Author(s):  
Frank C. Cackowski ◽  
Judith L. Anderson ◽  
Kenneth D. Patrene ◽  
Rushir J. Choksi ◽  
Steven D. Shapiro ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Angiogenic Factor ◽  
Adult Mice ◽  
Parathyroid Hormone Related Protein ◽  
Receptor Activator ◽  
Metalloproteinase 9

Abstract Increased osteoclastogenesis and angiogenesis occur in physiologic and pathologic conditions. However, it is unclear if or how these processes are linked. To test the hypothesis that osteoclasts stimulate angiogenesis, we modulated osteoclast formation in fetal mouse metatarsal explants or in adult mice and determined the effect on angiogenesis. Suppression of osteoclast formation with osteoprotegerin dose-dependently inhibited angiogenesis and osteoclastogenesis in metatarsal explants. Conversely, treatment with parathyroid hormone related protein (PTHrP) increased explant angiogenesis, which was completely blocked by osteoprotegerin. Further, treatment of mice with receptor activator of nuclear factor-κB ligand (RANKL) or PTHrP in vivo increased calvarial vessel density and osteoclast number. We next determined whether matrix metalloproteinase-9 (MMP-9), an angiogenic factor predominantly produced by osteoclasts in bone, was important for osteoclast-stimulated angiogenesis. The pro-angiogenic effects of PTHrP or RANKL were absent in metatarsal explants or calvaria in vivo, respectively, from Mmp9−/− mice, demonstrating the importance of MMP-9 for osteoclast-stimulated angiogenesis. Lack of MMP-9 decreased osteoclast numbers and abrogated angiogenesis in response to PTHrP or RANKL in explants and in vivo but did not decrease osteoclast differentiation in vitro. Thus, MMP-9 modulates osteoclast-stimulated angiogenesis primarily by affecting osteoclasts, most probably by previously reported migratory effects on osteoclasts. These results clearly demonstrate that osteoclasts stimulate angiogenesis in vivo through MMP-9.

scholarly journals Colony-Stimulating Factor-1 (CSF-1) Directly Inhibits Receptor Activator of Nuclear Factor-κB Ligand (RANKL) Expression by Osteoblasts

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 4977-4988 ◽  
Author(s):  
Y. Wittrant ◽  
Y. Gorin ◽  
S. Mohan ◽  
B. Wagner ◽  
S. L. Abboud-Werner
Keyword(s):  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Rankl Expression ◽  
Nadph Oxidase Activity ◽  
Rankl Mrna ◽  
Receptor Activator ◽  
Bone Marrow Cultures ◽  
Stimulating Factor

Colony-stimulating factor-1 (CSF-1), released by osteoblasts, stimulates the proliferation of osteoclast progenitors via the c-fms receptor (CSF-1R) and, in combination with receptor activator of nuclear factor-κB ligand (RANKL), leads to the formation of mature osteoclasts. Whether the CSF-1R is expressed by osteoblasts and mediates specific biological effects in osteoblasts has not been explored. Wild-type primary calvaria osteoblasts (OB) were analyzed for CSF-1R expression (RT-PCR and Western blot) and functionality (immunocomplex kinase assay). OB were serum starved for 24 h, and the effect of CSF-1 (0–100 ng/ml) on OB biological activities was determined at 48 h. In wild-type mouse bone marrow cultures, CSF-1 was tested for its effect on RANKL mRNA and osteoclast formation. Because ROS influence osteoblast RANKL expression, studies analyzed the effect of CSF-1 on reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and Nox1 and Nox4 proteins. Results indicate that OB express CSF-1R mRNA and protein and that CSF-1R could be phosphorylated in the presence of CSF-1. In osteoblasts, CSF-1 decreased RANKL mRNA in a dose- and time-dependent manner. Incubation of bone marrow cultures with CSF-1 resulted in a significant decline in tartrate-resistant acid phosphatase (TRACP) activity and CTR expression. RANKL-decreased expression by CSF-1 was correlated with a decrease of NADPH oxidase activity as well as Nox1 and Nox4 protein levels. These findings provide the first evidence that osteoblasts express CSF-1R and are a target for CSF-1 ligand. CSF-1-mediated inhibition of RANKL expression on osteoblasts may provide an important mechanism for coupling bone formation/resorption and preventing excessive osteoclastogenesis during normal skeletal growth.

scholarly journals Membrane Rafts Play a Crucial Role in Receptor Activator of Nuclear Factor κB Signaling and Osteoclast Function

2003 ◽  
Vol 278 (20) ◽  
pp. 18573-18580 ◽  
Author(s):  
Hyunil Ha ◽  
Han Bok Kwak ◽  
Seung Ku Lee ◽  
Doe Sun Na ◽  
Christopher E. Rudd ◽  
...  
Keyword(s):  
Crucial Role ◽  
Nuclear Factor Κb ◽  
Membrane Rafts ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
Osteoclast Function
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