Leptin Inhibits Osteoclast Generation

Holloway, Wayne R.; Collier, Fiona; Aitken, C. J.; Myers, Damian E.; Hodge, Jason M; Malakellis, Mary; Gough, Tamara J.; Collier, Gregory; Nicholson, Geoffrey C.

doi:10.1359/jbmr.2002.17.2.200

Cited by 382 publications

(278 citation statements)

References 52 publications

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“…Leptin increases OPG mRNA and protein expression in vitro [23][24][25]. However, in our study, there were negative correlations between serum OPG and leptin.…”

Section: Discussionmentioning

confidence: 51%

“…As to serum OPG levels in AN higher than those of controls, various hormones including estrogen, IGF-I, leptin and i-PTH are related to OPG and RANKL both in vitro and in vivo [10][11][12][13][21][22][23][24][25][26][27]. Seventeen βE2 dose-and time-dependently increase OPG mRNA and protein levels by the estrogen receptor-α (ERα) [10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

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The Relationship between Serum Levels of Estradiol and Osteoprotegerin in Patients with Anorexia Nervosa

et al. 2007

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Abstract. Osteoporosis is one of the major complications in anorexia nervosa (AN) patients. Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) have been identified as important regulators of bone turnover. The objective of this study was to clarify the role of RANK-RANKL-OPG system, and their relationship with other regulators for bone metabolism in AN patients. We investigated serum levels of RANKL, OPG, and bone turnover markers of 26 Japanese young female AN patients and 7 age-matched healthy women. We measured serum levels of estradiol (E2), insulin like growth factor-I (IGF-I) and triiodothyronin (T3) from the same samples and studied their relationship with RANKL or OPG. Mean serum levels of E2, IGF-I, T3 and leptin in AN patients were significantly lower than those of controls (p<0.05). Serum levels of OPG in AN patients were significantly higher than those in controls and negatively correlated with body mass index (BMI), E2, IGF-I or leptin. Serum levels of free RANKL could not be detected except for only one healthy control in both groups. These results suggest that serum OPG levels may be increased by a compensatory mechanism for malnutrition and estrogen deficiency which induces an increase in bone resorption. FIFTY percent of new AN outpatients show a decrease in lumbar bone mineral density (BMD) [1][2][3][4][5][6]. We have previously reported that the mechanism of osteoporosis in AN patients is both decreased bone formation and increased bone resorption due to decreased serum levels of insulin like growth factor-I (IGF-I) and estradiol (E2) [4,5]. Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) have been identified as important regulators of bone turnover [7][8][9]. RANKL is essential for osteoclast differentiation via its receptor located on the surface of osteoclast precursor cells. OPG is a soluble decoy receptor which inhibits osteoclast differentiation through its binding to RANKL. Estrogen negatively regulates osteoclast differentiation and proliferation via RANK-RANKL system, and increases osteoclast apoptosis. Estrogen also inhibits osteocyte apoptosis, maintains osteocyte viability, and stimulates osteoblast-like cells to produce OPG [10][11][12][13]. It is reported that serum levels of RANKL and OPG increased in postmenopausal women [14,15]. AN is accompanied with amenorrhea and demonstrates low serum levels of E2. Serum levels of OPG In AN patients have been already reported [16,17], but the results are controversial. The objective of this study is to clarify the role of RANK-RANKL-OPG system and their relationship with other regulators for bone metabolism in AN patients.

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“…Leptin increases OPG mRNA and protein expression in vitro [23][24][25]. However, in our study, there were negative correlations between serum OPG and leptin.…”

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

The Relationship between Serum Levels of Estradiol and Osteoprotegerin in Patients with Anorexia Nervosa

et al. 2007

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“…(27) This would imply that leptin, in addition to its central neuroendocrine effect, also directly influences bone cells. This indeed has been demonstrated in vitro because leptin can stimulate osteoblastic bone formation (28) and decrease osteoclastogenesis (29) and is now shown to be able to stimulate FGF-23 secretion. These favorable bone effects also were observed in vivo because leptin administration increased bone mass in estrogen-deficient rodents, (30) and circulating leptin was positively associated with bone mass in pre-and postmenopausal women.…”

mentioning

confidence: 79%

The white adipose tissue connection with calcium and bone homeostasis

Bouillon

Decallonne

2010

Journal of Bone and Mineral Research

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T he idea of fat cells and tissue being the passive storage site of excess energy has long been gone. Not surprisingly, fat cells (white adipose tissue) were first recognized as being the source of hormones controlling energy homeostasis because they secrete more leptin with increasing fat stores. (1) Leptin then crosses the blood-brain barrier to activate its receptor in the hypothalamic regions, thereby starting a complex feedback on energy intake and expenditure but also regulating other systems such as sexual maturation and reproduction (2) and bone homeostasis. (3) Indeed, a series of elegant studies of the Karsenty group clearly demonstrated that central activation of leptin signaling activates the sympathetic postganglionic neuronal system that ultimately decreases bone formation and increases bone resorption. (3,4) Leptin receptors are also found outside the hypothalamus in insulin-producing b cells, bone marrow stromal cells, osteoblasts and chondrocytes, and kidney cells. (5) This suggests a much wider spectrum of activities for this fat cell signal, not mediated by a central neuroendocrine system.A few years ago, Horiuchi's laboratory (6,7) described increased serum concentrations of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], calcium, and phosphate in leptin-deficient (ob/ob) mice owing to increased renal expression of CYP27B1 [¼ 25(OH)D 1a-hydroxylase] that could be corrected by intraperitoneal leptin injections. The same group (8) now expands this observation by demonstrating that leptin stimulates the osteoblast (osteocyte?) production of fibroblast growth factor 23 (FGF-23), which is thereafter responsible for the downregulation of CYP27B1 and of the sodium-phosphate cotransporters (NaPT-II). The overproduction of 1,25(OH) 2 D 3 also was present in mice with leptin receptor deficiency (db/db mice) but could not, in contrast to the ob/ob mice, be corrected by intraperitoneal leptin injection. FGF-23 therapy also corrected the overproduction of 1,25(OH) 2 D 3 in ob/ob mice (not reported for db/db mice). Addition of leptin to renal tubular cell cultures did not modify the local 1a-hydroxylase activity. (8) clearly demonstrating the indirect effects of leptin.What Are the Implications of These Observations?F irst, the new data further elucidate the complex regulation of the renal production of the vitamin D hormone. Indeed, it is now well established that calcium/calcium sensing receptordriven parathyroid hormone (PTH) secretion constitutes the major stimulus for renal 1a-hydroxylase and thus the production of systemic 1,25(OH) 2 D 3 while shutting down the expected renal activation of CYP24A1, the major degradation system for vitamin D metabolites. (9)(10)(11) The second systemic hormone, osteocytic FGF-23, is a negative regulator of renal 1a-hydroxylase activity, whereas both PTH and FGF-23 decrease the tubular reabsorption of phosphate by downregulation of NaPT-II. The PTH and FGF-23 hormones thus regulate vitamin D activation, as driven by calcium and phosphate, respectively (12)(13)(14) (Fig. 1...

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“…The best known of these adipokines is leptin, a hormone we have previously shown to correlate directly with body fat mass in these animals (Colman et al 1998). Locally, leptin is responsible for skeletal preservation by increasing osteoblast proliferation and differentiation (Thomas et al 1999) and inhibiting osteoclastogenesis (Holloway et al 2002). Indirectly, leptin may act on the skeleton through stimulation of growth hormone secretion and its effects on the hypothalamic-pituitary axis (Carro et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Skeletal effects of long-term caloric restriction in rhesus monkeys

Colman

Beasley

Allison

et al. 2011

AGE

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Age-related bone loss is well established in humans and is known to occur in nonhuman primates. There is little information, however, on the effect of dietary interventions, such as caloric restriction (CR), on age-related bone loss. This study examined the effects of long-term, moderate CR on skeletal parameters in rhesus monkeys. Thirty adult male rhesus monkeys were subjected to either a restricted (R, n0 15) or control (C, n015) diet for 20 years and examined throughout for body composition and biochemical markers of bone turnover. Total body, spine, and radius bone mass and density were assessed by dualenergy X-ray absorptiometry. Assessment of biochemical markers of bone turnover included circulating serum levels of osteocalcin, carboxyterminal telopeptide of type I collagen, cross-linked aminoterminal telopeptide of type I collagen, parathyroid hormone, and 25(OH)vitamin D. Overall, we found that bone mass and density declined over time with generally higher levels in C compared to R animals. Circulating serum markers of bone turnover were not different between C and R with nonsignficant diet-by-time interactions. We believe the lower bone mass in R animals reflects the smaller body size and not pathological osteopenia.

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Leptin Inhibits Osteoclast Generation

Cited by 382 publications

References 52 publications

The Relationship between Serum Levels of Estradiol and Osteoprotegerin in Patients with Anorexia Nervosa

The Relationship between Serum Levels of Estradiol and Osteoprotegerin in Patients with Anorexia Nervosa

The white adipose tissue connection with calcium and bone homeostasis

Skeletal effects of long-term caloric restriction in rhesus monkeys

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