scholarly journals Nitric Oxide Regulates Receptor Activator of Nuclear Factor-κB Ligand and Osteoprotegerin Expression in Bone Marrow Stromal Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 751-759 ◽  
Author(s):  
Xian Fan ◽  
Eileen Roy ◽  
Liping Zhu ◽  
Tamara C. Murphy ◽  
Cheryl Ackert-Bicknell ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Resorption ◽  
Sodium Nitroprusside ◽  
Bone Remodeling ◽  
Stromal Cells ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
No Donor ◽  
Positive Effects ◽  
Receptor Activator

Abstract Bone remodeling reflects an equilibrium between bone resorption and formation. The local expression of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) in bone determines the entry of monoblastic precursors into the osteoclast lineage and subsequent bone resorption. Nitric oxide (NO) inhibits osteoclastic bone resorption in vitro and regulates bone remodeling in vivo. An interaction of NO with RANKL and OPG has not been studied. Here, we show that treatment of ST-2 murine stromal cells with the NO donor sodium nitroprusside (100 μm) for 24 h inhibited 1,25 dihydroxyvitamin D3-induced RANKL mRNA to less than 33 ± 7% of control level, whereas OPG mRNA increased to 204 ± 19% of control. NOR-4 replicated these NO effects. The effects of NO were dose dependent and associated with changes in protein levels: RANKL protein decreased and OPG protein increased after treatment with NO. PTH-induced RANKL expression in primary stromal cells was inhibited by sodium nitroprusside, indicating that the NO effect did not require vitamin D. NO donor did not change the stability of RANKL or OPG mRNAs, suggesting that NO affected transcription. Finally, cGMP, which can function as a second messenger for NO, did not reproduce the NO effect, nor did inhibition of endogenous guanylate cyclase prevent the NO effect on these osteoactive genes. The effect of NO to decrease the RANKL/OPG equilibrium should lead to decreased recruitment of osteoclasts and positive bone formation. Thus, drugs and conditions that cause local increase in NO formation in bone may have positive effects on bone remodeling.

Macrophage inflammatory protein-1α is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor κB ligand

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3349-3353 ◽  
Author(s):  
Je-Ho Han ◽  
Sun Jin Choi ◽  
Noriyoshi Kurihara ◽  
Masanori Koide ◽  
Yasuo Oba ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Nuclear Factor Κb ◽  
Marrow Stromal Cells ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Myeloma Cells ◽  
Parathyroid Hormone Related Protein ◽  
Inflammatory Protein ◽  
Receptor Activator ◽  
Macrophage Inflammatory Protein

A complementary DNA expression library derived from marrow samples from myeloma patients was recently screened and human macrophage inflammatory protein-1α (hMIP-1α) was identified as an osteoclastogenic factor expressed in these samples. hMIP-1α enhanced osteoclast (OCL) formation in human marrow cultures and by highly purified OCL precursors in a dose-dependent manner (5-200 pg/mL). Furthermore, hMIP-1α enhanced OCL formation induced by human interleukin-6 (IL-6), which is produced by marrow stromal cells when they interact with myeloma cells. hMIP-1α also enhanced OCL formation induced by parathyroid hormone-related protein (PTHrP) and receptor activator of nuclear factor κB ligand (RANKL), factors also implicated in myeloma bone disease. Time-course studies revealed that the hMIP-1α acted during the last 2 weeks of the 3-week culture period. Reverse transcription–polymerase chain reaction analysis showed that the chemokine receptors for hMIP-1α (CCR1 and CCR5) were expressed by human bone marrow and highly purified early OCL precursors. Furthermore, hMIP-1α did not increase expression of RANKL. These data demonstrate that hMIP-1α is an osteoclastogenic factor that appears to act directly on human OCL progenitors and acts at the later stages of OCL differentiation. These data further suggest that in patients with myeloma, MIP-1α produced by myeloma cells, in combination with RANKL and IL-6 that are produced by marrow stromal cells in response to myeloma cells, enhances OCL formation through their combined effects on OCL precursors.

scholarly journals Overexpression of γ-Glutamyltransferase in Transgenic Mice Accelerates Bone Resorption and Causes Osteoporosis

Endocrinology ◽  
2007 ◽  
Vol 148 (6) ◽  
pp. 2708-2715 ◽  
Author(s):  
Kiyoshi Hiramatsu ◽  
Yutaro Asaba ◽  
Sunao Takeshita ◽  
Yuji Nimura ◽  
Sawako Tatsumi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Transgenic Mice ◽  
Bone Destruction ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Expression Cloning ◽  
Nuclear Factor ◽  
Receptor Activator

We previously identified γ-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. To examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages to receptor activator of nuclear factor-κB ligand, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased receptor activator of nuclear factor-κB ligand expression in marrow stromal cells and also stimulated osteoclastogenesis from bone marrow macrophages at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction and provides a new target for therapeutic intervention.

Path Analysis Identifies Receptor Activator of Nuclear Factor-κB Ligand, Osteoprotegerin, and Sclerostin as Potential Mediators of the Tophus-bone Erosion Relationship in Gout

2016 ◽  
Vol 43 (2) ◽  
pp. 445-449 ◽  
Author(s):  
Ashika Chhana ◽  
Opetaia Aati ◽  
Gregory D. Gamble ◽  
Karen E. Callon ◽  
Anthony J. Doyle ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Path Analysis ◽  
Bone Remodeling ◽  
Bone Erosion ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Tophaceous Gout ◽  
Receptor Activator ◽  
Multiple Regression Modeling ◽  
The Relationship

Objective.To determine the relationship between tophus, erosion and bone remodeling factors in gout.Methods.Computed tomography bone erosion and circulating bone factors were measured in adults with tophaceous gout. Multiple regression modeling and path analysis were used to determine predictors of erosion.Results.Tophus number, Māori or Pacific ethnicity, creatinine, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin were independently associated with erosion. Path analysis showed a direct effect of tophus number on erosion, partially mediated through OPG, RANKL, and sclerostin.Conclusion.Tophus number is strongly associated with bone erosion in gout. Circulating RANKL, OPG, and sclerostin are potential mediators of tophus-related erosion.

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