The role of serum osteoprotegerin and receptor–activator of nuclear factor-κB ligand in metabolic bone disease of women after obesity surgery

The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM) bone disease are not completely understood. Recent evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor, receptor activator of nuclear factor-κB ligand (RANKL), and interferon γ (IFN-γ) that strongly suppresses osteoclastogenesis. Using a coculture transwell system we found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes and similarly purified MM cells stimulated RANKL production in autologous T lymphocytes. In addition, either anti–interleukin 6 (anti–IL-6) or anti–IL-7 antibody inhibited HMCL-induced RANKL overexpression. Consistently, we demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7 levels were significantly higher in patients with MM. Moreover, we found that the release of IFN-γ by T lymphocytes was reduced in presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell–free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 μg/mL). Finally, RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at least in part in MM-induced osteolysis through the RANKL overexpression.

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The Role of miR-21 in Osteoblasts–Osteoclasts Coupling In Vitro

Cells ◽

10.3390/cells9020479 ◽

2020 ◽

Vol 9 (2) ◽

pp. 479 ◽

Cited By ~ 4

Author(s):

Agnieszka Smieszek ◽

Klaudia Marcinkowska ◽

Ariadna Pielok ◽

Mateusz Sikora ◽

Lukas Valihrach ◽

...

Keyword(s):

Cathepsin K ◽

Nuclear Factor Κb ◽

Tartrate Resistant Acid Phosphatase ◽

Type I ◽

Nuclear Factor ◽

Paracrine Signaling ◽

Receptor Activator ◽

The Impact

MiR-21 is being gradually more and more recognized as a molecule regulating bone tissue homeostasis. However, its function is not fully understood due to the dual role of miR-21 on bone-forming and bone-resorbing cells. In this study, we investigated the impact of miR-21 inhibition on pre-osteoblastic cells differentiation and paracrine signaling towards pre-osteoclasts using indirect co-culture model of mouse pre-osteoblast (MC3T3) and pre-osteoclast (4B12) cell lines. The inhibition of miR-21 in MC3T3 cells (MC3T3inh21) modulated expression of genes encoding osteogenic markers including collagen type I (Coll-1), osteocalcin (Ocl), osteopontin (Opn), and runt-related transcription factor 2 (Runx-2). Inhibition of miR-21 in osteogenic cultures of MC3T3 also inflected the synthesis of OPN protein which is essential for proper mineralization of extracellular matrix (ECM) and anchoring osteoclasts to the bones. Furthermore, it was shown that in osteoblasts miR-21 regulates expression of factors that are vital for survival of pre-osteoclast, such as receptor activator of nuclear factor κB ligand (RANKL). The pre-osteoclast cultured with MC3T3inh21 cells was characterized by lowered expression of several markers associated with osteoclasts’ differentiation, foremost tartrate-resistant acid phosphatase (Trap) but also receptor activator of nuclear factor-κB ligand (Rank), cathepsin K (Ctsk), carbonic anhydrase II (CaII), and matrix metalloproteinase (Mmp-9). Collectively, our data indicate that the inhibition of miR-21 in MC3T3 cells impairs the differentiation and ECM mineralization as well as influences paracrine signaling leading to decreased viability of pre-osteoclasts.

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Interleukin-6 Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclastogenesis by Diverting Cells into the Macrophage Lineage: Key Role of Serine727 Phosphorylation of Signal Transducer and Activator of Transcription 3

Endocrinology ◽

10.1210/en.2007-1719 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3688-3697 ◽

Cited By ~ 89

Author(s):

Laurence Duplomb ◽

Marc Baud’huin ◽

Céline Charrier ◽

Martine Berreur ◽

Valérie Trichet ◽

...

Keyword(s):

Osteoclast Differentiation ◽

Nuclear Factor Κb ◽

Mouse Bone Marrow ◽

Nuclear Factor ◽

Signal Transducer ◽

Blood Monocytes ◽

Receptor Activator ◽

Few Data ◽

Macrophage Lineage

Osteoclasts are bone-resorptive cells that differentiate from hematopoietic precursors upon receptor activator of nuclear factor κB ligand (RANKL) activation. Previous studies demonstrated that IL-6 indirectly stimulates osteoclastogenesis through the production of RANKL by osteoblasts. However, few data described the direct effect of IL-6 on osteoclasts. To investigate this effect, we used several models: murine RAW264.7 cells, mouse bone marrow, and human blood monocytes. In the three models used, the addition of IL-6 inhibited RANKL-induced osteoclastogenesis. Furthermore, IL-6 decreased the expression of osteoclast markers and up-modulated macrophage markers. To elucidate this inhibition, signal transducer and activator of transcription (STAT) 3, the main signaling molecule activated by IL-6, was analyzed. Addition of two STAT3 inhibitors completely abolished RANKL-induced osteoclastogenesis, revealing a key role of STAT3. We demonstrated that a basal level of phosphorylated-STAT3 on Serine727 associated with an absence of phosphorylation on Tyrosine705 is essential for osteoclastogenesis. Furthermore, a decrease of Serine727 phosphorylation led to an inhibition of osteoclast differentiation, whereas an increase of Tyrosine705 phosphorylation upon IL-6 stimulation led to the formation of macrophages instead of osteoclasts. In conclusion, we showed for the first time that IL-6 inhibits RANKL-induced osteoclastogenesis by diverting cells into the macrophage lineage, and demonstrated the functional role of activated-STAT3 and its form of phosphorylation in the control of osteoclastogenesis.

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Metabolic Bone Disease in the CAPD Patient

Peritoneal Dialysis International ◽

10.1177/089686088300301s08 ◽

1983 ◽

Vol 3 (1_suppl) ◽

pp. 24-26 ◽

Cited By ~ 3

Author(s):

Francisco Llach

Keyword(s):

Vitamin D ◽

Renal Osteodystrophy ◽

Bone Disease ◽

Metabolic Bone Disease ◽

Osteitis Fibrosa ◽

Prospective Evaluation ◽

Metabolic Bone ◽

Capd Patient

It seems that CAPD may improve some patients with osteomalacia but may be similar to hemodialysis in regard to osteitis fibrosa. However, long-term prospective evaluation of the incidence of bone disease in CAPD patients is necessary before we can determine how CAPD may alter the incidence and expression of renal osteodystrophy. We need more information before we can conclude that CAPD may improve pure osteomalacia. Finally, the data available are insufficient to clarify the role of vitamin D analogues in these patients.

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Parathyroid Hormone-Related Protein (PTHrP) Accelerates Soluble RANKL Signals for Downregulation of Osteogenesis of Bone Mesenchymal Stem Cells

Journal of Clinical Medicine ◽

10.3390/jcm8060836 ◽

2019 ◽

Vol 8 (6) ◽

pp. 836 ◽

Cited By ~ 3

Author(s):

Jeevithan Elango ◽

Saeed Ur Rahman ◽

Yves Henrotin ◽

José Eduardo Maté Sánchez de Val ◽

Bin Bao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Parathyroid Hormone ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Related Protein ◽

Bone Mesenchymal Stem Cells ◽

Parathyroid Hormone Related Protein ◽

Receptor Activator

A recent study reported the expression of receptor activator of nuclear factor-κB (RANK) in mesenchymal stem cells (MSCs) surface that negatively regulates osteogenesis of MSCs. Empirical evidence from the previous study confirmed the role of parathyroid hormone-related protein (PTHrP) in osteoblastogenesis. However, it is necessary to understand the paracrine role of PTHrP and RANKL for osteogenesis in order to explore the hidden secrets in bone biology. Considering the above concept, paracrine cues of soluble-receptor activator of nuclear factor-κB ligand (sRANKL) and PTHrP in osteogenic differentiation of MSCs were investigated. Our results confirmed that sRANKL increased the expression of surface-RANK in MSCs at the earlier stage of osteogenesis, which was downregulated later in differentiated MSCs. In contrast, RANKL expression was low at the earlier stage of MSCs proliferation and high at the differentiation stage of MSCs, which may play a fundamental role in osteoclast formation. sRANKL downregulated osteogenesis of MSCs by decreasing progressive ankylosis (ANK) protein expression while PTHrP upregulated the osteogenic exploitive effect of sRANKL. Interestingly, when they were co-cultured with MSCs, T-lymphocytes expressed high membrane-RANKL levels that contribute to osteogenesis inhibition during MSC differentiation. Thus, our results disclose that sRANKL treatment downregulates osteogenesis of MSCs by increasing RANK expression at the earlier stage of differentiation and by inhibiting ANK. Further, we demonstrated that PTHrP accelerated the downregulating osteogenic effect of sRANKL.

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