Leptin Acts as a Growth Factor on the Chondrocytes of Skeletal Growth Centers

Maor, Gila; Rochwerger, Miri; Segev, Yael; Phillip, Moshe

doi:10.1359/jbmr.2002.17.6.1034

Cited by 221 publications

(175 citation statements)

References 47 publications

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“…Intraarticular administration of leptin induced expression of IGF-1 and TGF␤ in rat chondrocytes at both the mRNA and protein levels. This stimulating effect may explain the enhanced proteoglycan synthesis observed in leptininjected rats, which may be further increased by the up-regulation of growth factor receptors, as was previously shown for IGF-1 receptor in leptin-stimulated mandibular condyles (45).…”

Section: Key Role Of Leptin In Oa 3125supporting

confidence: 59%

Evidence for a key role of leptin in osteoarthritis

Dumond¹,

Presle²,

Terlain³

et al. 2003

Arthritis & Rheumatism

498

416

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Objective. To evaluate the contribution of leptin (an adipose tissue-derived hormone) to the pathophysiology of osteoarthritis (OA), by determining the level of leptin in both synovial fluid (SF) and cartilage specimens obtained from human joints. We also investigated the effect of leptin on cartilage, using intraarticular injections of leptin in rats.Methods. Leptin levels in SF samples obtained from OA patients undergoing either knee replacement surgery or knee arthroscopy were measured by enzymelinked immunosorbent assay. In addition, histologic sections of articular cartilage and osteophytes obtained during surgery for total knee replacement were graded using the Mankin score, and were immunostained using antibodies to leptin, transforming growth factor ␤ (TGF␤), and insulin-like growth factor 1 (IGF-1). For experimental studies, various doses of leptin (10, 30, 100, and 300 g) were injected into the knee joints of rats. Tibial plateaus were collected and processed for proteoglycan synthesis by radiolabeled sulfate incorporation, and for expression of leptin, its receptor (ObRb), and growth factors by reverse transcriptasepolymerase chain reaction and immunohistochemical analysis.Results. Leptin was observed in SF obtained from human OA-affected joints, and leptin concentrations correlated with the body mass index. Marked expression of the protein was observed in OA cartilage and in osteophytes, while in normal cartilage, few chondrocytes produced leptin. Furthermore, the pattern and level of leptin expression were related to the grade of cartilage destruction and paralleled those of growth factors (IGF-1 and TGF␤1). Animal studies showed that leptin strongly stimulated anabolic functions of chondrocytes and induced the synthesis of IGF-1 and TGF␤1 in cartilage at both the messenger RNA and the protein levels.Conclusion. These findings suggest a new peripheral function of leptin as a key regulator of chondrocyte metabolism, and indicate that leptin may play an important role in the pathophysiology of OA.

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Section: Key Role Of Leptin In Oa 3125supporting

confidence: 59%

Evidence for a key role of leptin in osteoarthritis

Dumond¹,

Presle²,

Terlain³

et al. 2003

Arthritis & Rheumatism

498

416

View full text Add to dashboard Cite

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“…Both groups have found a negative calcium balance caused by renal calcium leak in such diabetic patients. Also, since leptin resistance is a feature of type-2 diabetes and several labs have indicated that leptin may be involved in the process of bone formation (Maor et al 2002, Tamasi et al 2003, a skeletal role for leptin in type-2 diabetes is a possibility. Two opposing mechanisms have been suggested: (1) leptin may work locally to promote osteoblastogenesis, and (2) leptin may work through a central hypothalamic relay to produce an osteoblastic inhibitory factor (Ducy et al 2000).…”

Section: Discussionmentioning

confidence: 99%

A novel rat model for the study of deficits in bone formation in type-2 diabetes

et al. 2007

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Background There is evidence to suggest that impairment in bone formation and/or turnover is associated with the metabolic abnormalities characteristic of type-2 diabetes mellitus. However, bone regeneration/repair in type-2 diabetes has not been modeled. Using Zucker Diabetic Fatty (ZDF) rats (a model of type-2 diabetes) for tibial distraction osteogenesis (DO), we hypothesized that bone formation within the distraction gap would be impaired.Animals and methods Rats were examined for body weight, glycosuria, and glycosemia to confirm the diabetic condition during the study. The rats received placement of the external fixators and osteotomies on the left tibia. Distraction was initiated the following day at 0.2 mm twice a day and continued for 14 days. The lengthened tibiae were harvested and distraction gaps were examined radiographically and histologically.Results We found significant reduction in new bone formation in the distraction gaps of the ZDF rats, both radiographically and histologically, compared to lean rats. We found a decrease in a marker of cellular proliferation in the distraction gaps and increased adipose volume in adjacent bone marrow of the ZDF rats.Interpretation Our findings suggest that this model might be used to study the contributions of leptin resistance, insulin resistance and/or hyperglycemia to impaired osteoblastogenesis in vivo.

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“…Antisense and sense probes for in situ hybridisation were produced by transcription using an RNA labelling kit (Sp6/T7 digoxigenin [DIG]-RNA; Boehringer, Mannheim, Germany) following the company's instructions. The transduced and untransduced hepatocytes were hybridised with sense and anti-sense DIG-labelled RNA probes as described [37]. Hybrids were detected using anti-DIG antibodies conjugated with rhodamine (Cat.…”

Section: Methodsmentioning

confidence: 99%

Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach

et al. 2006

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Aims/hypothesis We examined a clinical model of ex vivo transdifferentiation of primary adult hepatocytes to insulinsecreting cells for the treatment of type 1 diabetes. Materials and methods Isolated rat hepatocytes were transduced in primary culture with a human lentivirus containing pancreatic duodenal homeobox 1 (PDX1, now known as insulin promoter factor 1, homeodomain transcription factor [IPF1]). Insulin expression and secretion of the newly engineered cells were assessed in vitro by RT-PCR, in situ hybridisation, immunostaining and radioimmunoassay. PDX1-transduced hepatocytes were further studied in vivo by injecting them under the renal capsule of diabetic SCID mice. Results Isolated rat hepatocytes were efficiently transduced with the lentiviral vector, as assessed by green fluorescent reporter gene expression. The transduced cells exhibited insulin at both mRNA (RT-PCR, in situ hybridisation) and protein levels (immunostaining and radioimmunoassay). Moreover, insulin secretion by the engineered cells was dependent on glucose and sulfonylurea. Other beta cell genes, including those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (Slc2a2), glucokinase (Gck), ATP-binding cassette, sub-family C (CFTR/ MRP), member 8 (Abcc8), the potassium inwardly-rectifying channel, subfamily J, member 11 (Kcnj11) and proprotein convertase subtilisin/kexin type 1 (Pcsk1) were also expressed. The PDX1-transduced hepatocytes expressed several pancreatic transcription factors related to early pancreatic endocrine development (endogenous Pdx1, 6 transdifferentiated liver cells under the renal capsule of seven streptozotocin-induced diabetic SCID mice resulted in significant reduction of nonfasting blood glucose levels from 30.7 ± 1.3 to 8.7 ± 3.7 mmol/l (mean ± SEM, p=0.01), in 6 to 8 weeks. Removal of the graft resulted in severe hyperglycaemia. Conclusions/interpretation Ex vivo lentiviral-mediated PDX1 expression in isolated adult liver cells represents a potential model for type 1 diabetes mellitus therapy.

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Leptin Acts as a Growth Factor on the Chondrocytes of Skeletal Growth Centers

Cited by 221 publications

References 47 publications

Evidence for a key role of leptin in osteoarthritis

Evidence for a key role of leptin in osteoarthritis

A novel rat model for the study of deficits in bone formation in type-2 diabetes

Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach

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