Leptin receptor isoform expression in rat osteoblasts and their functional analysis

Lee, Yun‐Jung; Park, Jung Hyun; Ju, Sung-Kyu; You, Kwan‐Hee; Ko, Jea Seung; Kim, Hyun‐Man

doi:10.1016/s0014-5793(02)02889-2

Cited by 61 publications

(40 citation statements)

References 20 publications

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“…Therefore, although evidence for a role of the central and sympathetic nervous systems in mediating the suppressive actions of leptin on bone is compelling (Ducy et al 2000, Hamrick & Ferrari 2007, our data combined with that demonstrating that leptin enhances osteoblast number and activity in vitro (Thomas et al 1999, Lee et al 2002 indicate that a positive direct action of leptin in bone cannot be excluded.…”

Section: Discussionmentioning

confidence: 81%

“…Supra-physiological levels of leptin are thought to suppress bone formation by a centrally mediated pathway involving the hypothalamus and the sympathetic nervous system (Ducy et al 2000, Hamrick & Ferrari 2007, while leptin within the normal range increases osteoblast number and enhances osteoblast activity via a direct mechanism (Thomas et al 1999, Lee et al 2002. Indeed, it has been reported that the leptin receptor (Hamrick et al 2005) and even leptin itself (Laharrague et al 1998) are both expressed in bone.…”

Section: Discussionmentioning

confidence: 99%

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The influence of leptin on trabecular architecture and marrow adiposity in GH-deficient rats

Evans

Bull²,

Kench³

et al. 2010

Journal of Endocrinology

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The relationship between the degree of GH deficiency and impaired bone integrity is not simple and may be influenced by related endocrine variables. To test the hypothesis that elevated adiposity and hyperleptinaemia are contributory factors, we quantified femoral trabecular organisation in two models of GH deficiency with divergent degrees of adiposity -the moderately GH-deficient/hyperleptinaemic transgenic growth retarded (Tgr) rat and the profoundly GH-deficient/ hypoleptinaemic dw/dw rat. Trabecular density (bone volume/total volume) and surface were reduced by 16% in dw/dw males, with a more fragmented trabecular lattice. This impairment was more pronounced in Tgr rats, with trabecular number and density further reduced (by an additional 21%) and relative surface (bone surface/bone volume), trabecular convexity (structural modal index) and fragmentation (pattern factor) increased. To establish whether the presence of obesity/hyperleptinaemia exacerbates bone impairment in GH deficiency, trabecular structure was assessed in dw/dw rats following diet-induced obesity (DIO). DIO had minimal effect on trabecular architecture, the increased concavity of trabecular surfaces being the only observable effect. Similarly, infusion of leptin into the tibial bone marrow cavity had no effect on trabecular organisation or tibial growth in wild-type rats. However, while this procedure also failed to affect trabecular architecture or osteoclast number in dw/dw rats, distal osteoblast surface was increased by 23%, marrow adipocyte number and epiphyseal plate width being reduced (by 40 and 5% respectively), without increasing caspase-3 immunoreactivity. These findings suggest that while leptin may directly inhibit adipocyte differentiation and favour osteoblast production, hyperleptinaemia makes only a minimal contribution to the impairment of bone structure in GH deficiency.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

The influence of leptin on trabecular architecture and marrow adiposity in GH-deficient rats

Evans

Bull²,

Kench³

et al. 2010

Journal of Endocrinology

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“…vator SRC-1 and osteogenic transcription factor Runx2, transactivates osteocalcin, one of the Runx2 downstream target genes that may in turn mediate the osteogenic activity of leptin. STAT3 plays an essential role during embryonic development, cell survival, and differentiation (39). At the molecular level, STAT3 acts as a transcription activator and interacts with other nuclear factors to regulate a number of genes that are critically involved in cell proliferation and differentiation (40,41).…”

Section: Discussionmentioning

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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“…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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Leptin receptor isoform expression in rat osteoblasts and their functional analysis

Cited by 61 publications

References 20 publications

The influence of leptin on trabecular architecture and marrow adiposity in GH-deficient rats

The influence of leptin on trabecular architecture and marrow adiposity in GH-deficient rats

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

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

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