The leptin receptor in human osteoblasts and the direct effect of leptin on bone metabolism

Iwamoto, Ichiro; Fujino, Toshinori; Douchi, Tsutomu

doi:10.1080/09513590412331284389

Cited by 45 publications

(28 citation statements)

References 21 publications

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“…Several groups have reported the presence of a functional leptin receptor in cells within the osteoblast lineage [Steppan et al, 2000;Reseland et al, 2001;Cornish et al, 2002;Lee et al, 2002;Wamoto et al, 2004]. One other group, however, was unable to show the presence of leptin receptors and/or a functional response to leptin in osteoblast cultures [Ducy et al, 2000].…”

Section: Discussionmentioning

confidence: 94%

Leptin effect on RANKL and OPG expression in MC3T3‐E1 osteoblasts

Lamghari¹,

Tavares²,

Camboa³

et al. 2006

J of Cellular Biochemistry

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Recent studies have suggested that leptin hormone may play a pivotal role on bone remodeling through a direct effect by modulating positively the OPG/RANKL balance. Here, we investigate the effect of leptin hormone on RANKL and OPG expression in MC3T3-E1 osteoblasts using RT-PCR and ELISA measurements. We have at first identified the expression of Ob-Rb and Ob-Ra leptin receptor isoforms in MC3T3-E1 and observed that these cells respond to mrleptin treatments. We then investigated the effect of mrleptin on RANKL and OPG expression. We show that mrleptin dose-dependently regulated the expression of RANKL mRNA with complete inhibition observed at concentrations higher than 12 ng/ml. This effect was confirmed with sRANKL protein measurements. However, the exposure of MC3T3-E1 to mrleptin had no effect on OPG mRNA. Taken together, these results suggest that leptin modulates positively OPG/RANKL balance by inhibiting the expression of RANKL gene.

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Section: Discussionmentioning

confidence: 94%

Leptin effect on RANKL and OPG expression in MC3T3‐E1 osteoblasts

Lamghari¹,

Tavares²,

Camboa³

et al. 2006

J of Cellular Biochemistry

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“…Evidence has been provided that leptin is expressed in and secreted from human osteoblasts in primary culture (27)(28)(29), and that functionally active leptin-receptor isoforms are present in human osteoblast-derived cell lines and rat osteoblasts (30,31). Leptin was found to enhance human marrow stromal cell differentiation into osteoblasts (32), to stimulate proliferation of cultured osteoblasts, and to promote matrix production and mineralization (27)(28)(29). In contrast, in vivo studies evidenced an inhibitory effect of leptin on bone formation (33).…”

Section: Discussionmentioning

confidence: 99%

“…Such peptides include substance-P, VIP, CGRP and neuropeptide-Y (25,26), as well as leptin and the endogenous ligand of growth hormone secretagogue (GHS) receptor ghrelin, which, like orexins, play a major role in the central control of energy homeostasis. Evidence has been provided that leptin is expressed in and secreted from human osteoblasts in primary culture (27)(28)(29), and that functionally active leptin-receptor isoforms are present in human osteoblast-derived cell lines and rat osteoblasts (30,31). Leptin was found to enhance human marrow stromal cell differentiation into osteoblasts (32), to stimulate proliferation of cultured osteoblasts, and to promote matrix production and mineralization (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Cultured rat calvarial osteoblast-like cells are provided with orexin type 1 receptors

Ziółkowska¹,

Ruciński²,

Tortorella³

et al. 2007

Int J Mol Med

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Abstract. Orexins A and B are hypothalamic peptides which are derived from the proteolytic cleavage of prepro-orexin and act via two subtypes of receptors, named OX1-R (that almost exclusively binds orexin-A) and OX2-R (nonselective for both orexins). Several lines of evidence show that other neuropeptides, which like orexins are involved in the central control of energy homeostasis (e.g. leptin and ghrelin), may play a role in the regulation of bone metabolism, acting via autocrine-paracrine or endocrine routes. Therefore, we studied by reverse transcription-polymerase chain reaction (RT-PCR) the expression of the orexin system in rat calvarial osteoblastlike (ROB) cells, whose osteoblastic lineage was immunocytochemically demonstrated by their osteonectin and collagen-1α content at day 14 of culture. Conventional PCR detected the mRNA expression of OX1-R, but not OX2-R and prepro-orexin in ROB cells at days 2, 7 and 21 of culture. Semiquantitative real time-PCR evidenced a gradual downregulation of OX1-R mRNA in relation to the duration of culture. This novel finding suggests that rat osteoblasts could be a target for circulating orexin-A, especially during their early stages of differentiation into mature osteoblasts.

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“…After removal of MTT, 150 l of Me 2 SO were added to the cells, and the plates were shaken at room temperature for 10 min. The absorbance was measured at 540 nm using a microplate reader (7).…”

Section: Clinical Diagnosis and Spinal Ligament Samples-mentioning

confidence: 99%

“…A common feature of obese people is hyperleptinemia (5). Leptin, an adipocyte-derived cytokine, can stimulate the proliferation and osteogenic differentiation of various cell lines, such as the embryonic cell line C3H10T1/2, human NHOst cells, and human osteoblastic cells (6,7). However, the molecular mechanism underlying the osteogenic effect of leptin in TOLF is not totally understood.…”

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confidence: 99%

Mechanistic Roles of Leptin in Osteogenic Stimulation in Thoracic Ligament Flavum Cells

Fan

Chen

et al. 2007

Journal of Biological Chemistry

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Obesity is a risk factor for thoracic ossification of ligament flavum (TOLF) that is characterized by ectopic bone formation in the spinal ligaments. Hyperleptinemia is a common feature of obese people, and leptin, an adipocyte-derived cytokine with proliferative and osteogenic effects in several cell types, is believed to be an important factor in the pathogenesis of TOLF. However, how leptin might stimulate cell osteogenic differentiation in TOLF is not totally understood. We reported here that leptin-induced osteogenic effect in TOLF cells is associated with activation of signaling molecules STAT3, JNK, and ERK1/2 but not p38. Blocking STAT3 phosphorylation with a selective inhibitor, AG490, significantly abolished leptin-induced osteogenic differentiation of TOLF cells, whereas blocking ERK1/2 and JNK phosphorylation with their selective inhibitors PD98059 and SP600125, respectively, had only marginal effects. In addition, we showed that STAT3 interacted with Runt-related transcription factor 2 (Runx2) in the nucleus, and STAT3, Runx2, and steroid receptor coactivator steroid receptor coactivator-1 were components of the transcription complex recruited on Runx2 target gene promoters in response to leptin treatment. Our experiments identified STAT3, Runx2, and steroid receptor coactivator-1 as critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF. Ossification of ligament flavum (OLF)3 of the spine is characterized by a heterotopic bone formation in the ligament flavum that is normally composed of fibrous tissues (1). Ossification could enlarge the spinal canal and compresses the spinal cord, resulting in serious neurological damages. Epidemiology has shown that high incidence rate of OLF occurs in thoracic spine (2). It has been documented that obesity represents a risk factor for thoracic ossification of ligament flavum (TOLF), particularly in Asian people (3). Indeed, hereditary obese rats, Zucker fatty (fa/fa) rats, are prone to OLF (4). A common feature of obese people is hyperleptinemia (5). Leptin, an adipocyte-derived cytokine, can stimulate the proliferation and osteogenic differentiation of various cell lines, such as the embryonic cell line C3H10T1/2, human NHOst cells, and human osteoblastic cells (6, 7). However, the molecular mechanism underlying the osteogenic effect of leptin in TOLF is not totally understood.Leptin exerts its biological activity through binding to its receptors, which belong to cytokine receptor superfamily. Different leptin receptor isoforms exist, including a long form (ObRb) and a short form (ObRa) (8). In vitro and in vivo studies have shown that leptin activates cytokine-like signal transduction via the long form receptor. Upon leptin stimulation, intracellular Janus tyrosine kinases are activated via transphosphorylation and phosphorylate tyrosine residues on the long form leptin receptor and on signal transducers and activators of transcription (STAT) proteins (9). Phosphorylated STAT proteins dimerize and translocate to the nucleus to activate ge...

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The leptin receptor in human osteoblasts and the direct effect of leptin on bone metabolism

Cited by 45 publications

References 21 publications

Leptin effect on RANKL and OPG expression in MC3T3‐E1 osteoblasts

Leptin effect on RANKL and OPG expression in MC3T3‐E1 osteoblasts

Cultured rat calvarial osteoblast-like cells are provided with orexin type 1 receptors

Mechanistic Roles of Leptin in Osteogenic Stimulation in Thoracic Ligament Flavum Cells

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