Bone metabolism and adipokines: are there perspectives for bone diseases drug discovery?

Review

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 08/01/14 For personal use only.

Bone metabolism and adipokines: are there perspectives for bone diseases drug discovery? 1.

Introduction

2.

Leptin

3.

Adiponectin

4.

Visfatin

5.

Resistin

6.

Adipokines and fracture risk

7.

Other adipokines

8.

Conclusion

9.

Expert opinion

Morena Scotece, Javier Conde, Vanessa Abella, Verońica Lo´pez, Jes us Pino, Francisca Lago, Juan J Go´mez-Reino & Oreste Gualillo† †

Santiago University Clinical Hospital, SERGAS, Division of Rheumatology, Research Laboratory 9, Santiago de Compostela, Spain

Introduction: Over the past 20 years, the idea that white adipose tissue (WAT) is simply an energy depot organ has been radically changed. Indeed, present understanding suggests WAT to be an endocrine organ capable of producing and secreting a wide variety of proteins termed adipokines. These adipokines appear to be relevant factors involved in a number of different functions, including metabolism, immune response, inflammation and bone metabolism. Areas covered: In this review, the authors focus on the effects of several adipose tissue-derived factors in bone pathophysiology. They also consider how the modification of the adipokine network could potentially lead to promising treatment options for bone diseases. Expert opinion: There are currently substantial developments being made in the understanding of the interplay between bone metabolism and the metabolic system. These insights could potentially lead to the development of new treatment strategies and interventions with the aim of successful outcomes in many people affected by bone disorders. Specifically, future research should look into the intimate mechanisms regulating peripheral and central activity of adipokines as it has potential for novel drug discovery. Keywords: adipokines, bone, fat mass, osteoporosis Expert Opin. Drug Discov. (2014) 9(8):945-957

1.

Introduction

White adipose tissue (WAT) is now recognized to be not only an energy-storing organ but also a multifactorial organ capable of secreting several adipose-derived factors that have been termed collectively as ‘adipokines’ [1]. These molecules participate in the interaction between adipose tissue, inflammation and immunity. Adipokines are implicated through endocrine, paracrine, autocrine or juxtacrine crosstalk in a great variety of physiological or physiopathological processes, including food intake, insulin sensitivity, immunity and inflammation [2,3]. Recent experimental studies suggest that adipokines may also participate in the complex mechanism that regulates skeleton biology, both at bone and cartilage levels. In fact, adipose tissue, and consequently secreted adipokines, may regulate bone metabolism and be involved in the pathogenesis and progression of osteoporosis. Osteoporosis is a bone disease characterized by low bone mass and consequent increase in bone fragility and susceptibility to fracture. Although this bone degenerative disease is attributed to various factors, regulation of bone mass is the main determinant in the development of disease [4]. Several evidence showed that a positive correlation between bone mineral density (BMD) and fat mass [5-8] exists, suggesting a potential role of adipokines in bone metabolism. 10.1517/17460441.2014.922539 © 2014 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted

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might contribute to the sex-related higher incidence of certain diseases, such as osteoarthritis [18].

Article highlights. . .


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White adipose tissue (WAT) is no longer considered a mere energy depot. WAT produces and secretes a wide variety of proteins termed adipokines thought to be involved in a number of different functions, including metabolism, immune response, inflammation and bone metabolism. Leptin influences bone metabolism, but its implication is controversial. Adiponectin participates in the balance of bone resorption and bone formation. Visfatin could affect osteoblast differentiation, whereas resistin could contribute to bone metabolism and remodeling. Regulating adipokines presents a number of useful therapeutic options for bone disease.

This box summarizes key points contained in the article.

Therefore, the purpose of this review is to report the most recent findings about the role of adipokines in bone metabolism, focusing our attention on one of the most common bone disease: osteoporosis. 2.

Leptin

Leptin (LEP) is a 16 kDa protein described for the first time in 1994 [1]. LEP is the first and the best characterized member of the adipose tissue-derived hormones that have been termed collectively as ‘adipokines’. Under certain circumstances, leptin is also produced at low levels by other tissues, rather than WAT, such as intestine, placenta, mammary glands, gastric epithelium, skeletal muscle and brain [9], and by joint and bone tissues [10-15]. Leptin receptor (OB-R) is encoded by the diabetes gene and belongs to the class I cytokine receptor family. Six alternatively spliced isoforms of OB-R have been identified. These isoforms contain identical extracellular binding domain but differ by the length of cytoplasmic domains: a long isoform (OB-Rb), four short isoforms (OB-Ra, OB-Rc, OB-Rc and OB-Rf), and soluble isoform (OB-Re). However, only the long form (OB-Rb), which has the full intracellular domain, with the typical signaling elements of cytokine receptors, is capable of transducing the leptin signal to the nucleus. Leptin circulates both as a biologically active free form and a presumably inactive bound form associated with plasma proteins and the soluble leptin receptor (LEPR) isoform OB-Re [16]. In physiological conditions, circulating levels of leptin correlate positively with the amount of adipose tissue and body mass index (BMI) as well as with leptin mRNA and protein levels in adipose tissue [17]. This hormone acts in the brain as a regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexigenic factors and suppressing orexigenic neuropeptides. Leptin levels are gender-dependent and are higher in women than in men even when adjusted for BMI, which 946

Leptin and bone Several studies reported a positive correlation between fat mass and BMD and that fat accumulation might affect bone metabolism [19,20]. In fact, one of the main determinants of bone density and fracture risk is body weight, and adipose tissue is a major contributor to this relationship. Although there are a series of studies disclosing the role of leptin in bone metabolism, this effect remains controversial. Most of the in vitro studies argue that leptin increases osteoblastic proliferation and differentiation and inhibits adipogenic differentiation of bone marrow cells. On the other side, some lines of evidence demonstrate either no effect or a proapoptotic action of leptin on stromal cells. In a similar way, in vivo works demonstrated both positive and negative effects of leptin on bone mass. In vivo, the majority of the works suggest a negative role of leptin by enhancing sympathetic output to bone from the hypothalamus by suppressing serotonin (5HT) system in the brainstem. According to these data, leptin, secreted from adipose tissue, crosses the blood-- brain barrier and acts through the LEPR to inhibit 5HT production in containing neurons in the brainstem [21,22]. Normally, 5HT would be secreted from these nerve terminals in the ventromedial hypothalamus to suppress sympathetic activity to bone. However, under leptin-induced inhibition of 5HT synthesis, the sympathetic nervous system signals to osteoblasts by releasing norepinephrine onto b2 adrenergic receptors. This, in turn, suppresses bone formation and increases resorption through increased RANK ligand expression [23]. In summary, some works showed a very attractive mechanism for leptin-dependent regulation of bone mass, whereas other laboratories reported controversial data [24-26]. This may be due to confounding factors such as differences in histomorphometric or microarchitectural parameters. In any case, two main hypotheses of the role of leptin on bone metabolism are emerging: the first is based on a direct regulation that is due to increased osteoblast proliferation and differentiation [27] and the second through an indirect suppression of bone formation via a hypothalamic control (Figure 1). Anyway, we have to bear in mind one relevant aspect when we compare leptin actions on bone in humans and rodents, that is, leptin resistance. This term is used to describe the failure of leptin levels (endogenous or exogenous) to reduce food intake and body mass. Actually, obese individuals have high circulating leptin, but any or few responsiveness to leptin. Thus, as mentioned above, low leptin levels may have a more biologically significant effect than high leptin levels [28], suggesting that most of obese individuals are leptin-resistant, making the interpretation of the studies on the effects of leptin on bone a very tricky task. Based on the most experiments conducted on rodent, one would expect 2.1

Expert Opin. Drug Discov. (2014) 9(8)

Bone metabolism and adipokines

Ob-Rb

Leptin

Mesenchymal stem cell Adipose tissue

VMH nuclei

ARC nuclei

GTG-sensitive neurons

CART

tin

Lep


Hypothalamus

OPG Adrβ2 Osteoblast +

Rankl

Osteoblast

RANKL

Regulation of bone mass: -bone formation -bone resorption Hematopoietic stem cell

Osteoclast

Osteoclast Bone

Figure 1. Schematic representation of the potential mechanisms involved in leptin direct and indirect regulation of bone turnover. ARC nuclei: Hypothalamic arcuate nuclei; CART: Cocaine-amphetamine regulatory transcript; GTG-sensitive neurons: Glutamate-sensitive neurons; OPG: Osteoprotegerin; VMH nuclei: Entromedial hypothalamic nuclei.

that hyperleptinemia in obese animals would cause bone loss, but, surprisingly, this is not the case. Very recently, Maggio et al. showed that BMD was higher in obese adolescents and was associated with higher serum leptin concentrations [29]. So, the effects of leptin on bone exist but the truly mechanism is far to be determined and surely further experiments are needed to understand how leptin may impact the bone turnover in physiological and/or pathological conditions. Leptin might be associated with osteoporosis, a skeletal disease that is characterized by skeletal degeneration with low bone mass, which predisposes a person to an increased risk of fractures. As mentioned above, fat mass correlates with BMD. Some studies suggested that body weight, or high BMI, correlates with high BMD in both men and women. On the contrary, lower weight and low BMI were associated with a loss of bone mineral [30-33]. However, the adipose mass being a component of total body weight, some epidemiological and clinical studies support, on the contrary, an inverse correlation between high level of fat mass and BMD. Thus, fat accumulation might be considered as a risk factor for osteoporosis and fragility fractures [19,20,34-36].

Moreover, in animal experimental studies, it has been observed that suppressor of cytokine signaling-3 (SOCS-3) knockout (KO) mice, a mutation that leads to a partial gain of function in leptin signaling, showed normal appetite control but an osteoporotic phenotype [37,38]. Serum leptin may be a useful indicator of risk for osteoporosis associated with dietinduced obesity. In a study by Fujita et al., it has been reported that serum leptin level increased significantly in mice fed with a high-fat diet compared with age-matched normal diet-fed control mice. These authors found that leptin was negatively correlated with trabecular bone density and was positively correlated with cortical bone cross-sectional area, suggesting that leptin might regulate bone turnover differentially in these two bone compartments [39]. In addition, in older patients with hip fracture, serum leptin concentrations were directly associated with osteocalcin, an osteoblast-specific protein, used as a biochemical marker for bone formation [40]. Recently, Campos et al. reported that leptin:adiponectin ratio is a negative predictor of BMD and bone mineral content (BMC), showing that increase values of that variable promote decreased BMD and BMC values in obese adolescent girls [41]. Other studies investigated the association between leptin and bone mass through the analysis of LEPR gene expression.


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In a recent study, Lee et al. suggested that LEPR c.1968G>C polymorphism may be one of the genetic factors affecting femoral neck BMD in postmenopausal Korean women [42]. In addition, recent data indicated that LEP and LEPR polymorphisms might play important roles in the pathogenesis of osteoporosis by activating the secretion of proinflammatory cytokines, such as IL-6 and TNF-a [43]. Leptin might modulate a series of genes, such as alkaline phosphatase and osteocalcin, implicated in ossification, promoting bone mineralization, remodeling, resorption and osteoblast differentiation [44]. Finally, Liu et al. showed that leptin can promote osteoblastic differentiation of calcifying vascular smooth muscle cells from female mice by two pathways: OB-Rb/Extracellular signal-regulated kinases 1 and 2 (ERK 1/2)/nuclear factor kB ligand (RANKL)-BMP4 and OB-Rb/ phosphoinositide 3 kinase (PI3K)/Akt/RANKL-BMP4 [45]. 3.

Adiponectin

Adiponectin, also known as GBP28, apM1, Acrp30 or AdipoQ, is a 244-residue protein with structural homology to types VIII and X collagen and complement factor C1q that is prevalently synthesized by adipose tissue. Adiponectin circulates in the blood in large amounts and constitutes approximately 0.01% of the total plasma proteins and can be found as different molecular forms (trimers, hexamers and also 12-18-monomer forms) [46,47]. The gene that codes for human adiponectin is located on chromosome 3q27, a locus linked with susceptibility to diabetes and cardiovascular diseases [48]. Ablation of the adiponectin gene has no dramatic effect on KO mice on a normal diet, but when placed on a high fat/sucrose diet, animals develop severe insulin resistance and exhibit lipid accumulation in muscles [49]. Circulating adiponectin levels tend to be low in morbidly obese patients and increase with weight loss and with the use of thiazolidinediones (PPAR agonists) which enhance sensitivity to insulin [46,50]. Adiponectin decreases insulin resistance by stimulating glucose uptake, by increasing fatty acid oxidation and reducing the synthesis of glucose in the liver and other tissues [46]. Adiponectin acts via two receptors, one (AdipoR1) found predominantly in skeletal muscle and the other (AdipoR2) in liver. Transduction of the adiponectin signal by AdipoR1 and AdipoR2 involves the activation of AMPK, PPAR-a, PPAR-g and other signaling molecules [46]. To note, targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and all its metabolic actions [51]. Adiponectin and bone Some studies [52,53] have supported a functional role for adiponectin in bone biology, showing that this adipokine and its receptors are expressed in osteoblasts [54], which also differentiate in response to this hormone. In fact, this adipokine was capable of stimulating the proliferation and mineralization of human osteoblasts via the p38 MAPK signaling pathway in autocrine and/or paracrine manners [55,56]. 3.1

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Moreover, adiponectin enhanced bone morphogenetic protein 2 (BMP-2) expression that was demonstrated to play a crucial role in osteoblast differentiation and bone formation in cultured osteoblastic cells [57]. In line with this, it was described that adiponectin inhibited differentiation of bone marrow macrophages and CD14+ mononuclear cells into osteoclasts [52]. In contrast, adiponectin indirectly activates osteoclasts by stimulating RANKL and inhibiting osteoprotegerin production in osteoblasts [58]. In vitro studies also showed that adiponectin was able to induce VEGF, MMP-1, MMP-13, IL-6 and IL-8 in cultured osteoblasts [59], revealing an important role for adiponectin in joint destruction by inducing these catabolic and proinflammatory mediators in osteoblasts (Figure 2). In vivo studies highlighted interesting but controversial results. Oshima et al. reported that mice treated with adiponectin showed increased trabecular bone mass and decreased number of osteoclasts [52]. In line with this, another group demonstrated that adiponectin produced an increase in bone mass in mice and this effect occurred through an adipokinemediated decrease of the sympathetic tone, by acting on neurons of locus coeruleus [60]. However, these authors also showed that adiponectin inhibits osteoblast differentiation and promotes their apoptosis [60]. These results demonstrated that adiponectin could act in two different manners depending on the site of action. On the other hand, another study revealed that adiponectin KO mice displayed increased bone mass [61]. Moreover, adiponectin deficiency can protect against osteoporosis in ovariectomized mice [62]. Altogether, these data suggest that adiponectin participates in the balance of bone formation and bone resorption. However, more studies will be necessary to clarify the exact role of this adipokine in bone metabolism. Clinical studies also support the concept of adiponectin as a bone metabolism regulator. Several studies have demonstrated an inverse relationship between adiponectin plasma concentration and total body BMD in adult men and women, also after adjustment for fat mass [8,63]. Other reports also showed a negative correlation between adiponectin levels and BMD in men over 60 years, which was even stronger when BMI exceeded 27 kg/m2 [64]. This inverse association was also observed in healthy young men at the time of peak bone mass [65]. Other clinical articles revealed an association between total and high molecular weight adiponectin levels and vertebral fractures in men with type 2 diabetes [66] but not in elderly men [67]. Interestingly, Kanazawa et al. demonstrated that baseline serum total adiponectin levels in type 2 diabetes mellitus patients after 1 year of treatment with insulin or with oral hypoglycemic agents was significantly and positively correlated with percentage change in femoral neck BMD [68]. Ethnicity could also be a relevant factor to consider in the relationship between adiponectin and BMD. In fact, adiponectin was inversely correlated with BMD in Caucasian but not in Hispanic women [69]. Very recently, Okuno et al. have reported that an increased serum adiponectin was associated with decreased BMD in




Adipose tissue

Adiponectin

RANKL VEGF, MMP-1, MMP-13 IL-6 and IL-8 BMP-2

OPG

Proliferation and mineralization of osteoblasts Osteoclast activation

Figure 2. Schematic representation of regulation of bone metabolism by adiponectin. BMP-2: Bone morphogenetic protein 2; OPG: Osteoprotegerin.

male hemodialysis patients, suggesting a potential role of adiponectin in the mineral and bone disorders observed in patients with chronic renal failure [70]. These studies demonstrated that adiponectin was the most relevant adipokine negatively associated with BMD, independently of gender, menopausal status and fat mass parameters [63]. However, the increase in adiponectin levels was hypothesized as a physiological compensation and adaptation to low BMD status [68]. 4.

Visfatin

producing cells [73,74]. Macrophages have been also described as a source of visfatin production [75]. It is supposed that visfatin has insulin mimetic properties, but the role of this adipokine in glucose metabolism is still unclear [72,76]. Visfatin is upregulated in models of acute injury and sepsis [77], and its synthesis is regulated by factors such as glucocorticoids, TNF-a, IL-6 and growth hormone. Moreover, visfatin has been shown to induce chemotaxis and to produce IL-1b, TNF-a, and IL-6 in lymphocytes [78]. Visfatin and bone It has been described that visfatin influenced cell proliferation, glucose uptake and collagen type I synthesis in osteoblasts [79]. Moreover, visfatin knockdown inhibited osteoclast formation [80]. Apart from these effects, the relationship between this adipokine and BMD has also been studied. However, data so far available present some discrepancies and the potential involvement of visfatin in bone metabolism still remains unclear. Some studies showed that visfatin did not represent an independent predictor of BMD, due to the absence of any correlation between these two parameters [81-83], and 4.1

Visfatin, also called pre-B-cell colony-enhancing factor and nicotinamide phosphoribosyltransferase, is a protein of approximately 471 amino acids and 52 kDa [71]. It is a hormone that originally was discovered in liver, bone marrow and muscle, but it is also secreted by visceral fat [71,72]. It has been reported that visfatin levels are increased in obesity. Moreover, leukocytes from obese patients produce higher amounts of visfatin compared with lean subjects and, specifically, granulocytes and monocytes are the major


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even a recent study, developed to elucidate a relationship between visfatin and BMD in postmenopausal women, did not reveal any correlation within these two factors [84]. On the other hand, another group found a positive correlation between visfatin and BMD [85], whereas other authors reported a negative correlation between these two factors [86]. Differences in sample collection and patient recruitment used in these studies might be the reason for the discrepancies observed. Anyway, adipose tissue has been suggested to influence bone metabolism and density through the action of adipokines such as visfatin. In fact, it was very recently proposed that visfatin could exert positive effects on fetal/neonatal bone metabolism [87]. Senile osteoporosis is related with a progressive decrease in bone mass and higher accumulation of marrow fat. The marrow adipocytes and osteoblasts share the same cellular progenitor and in vitro studies showed that visfatin activity could influence the differentiation of mesenchymal stem cells to adipocytes or osteoblasts [88]. This result reveals a possible role of visfatin in the development of senile osteoporosis. Moreover, it has been reported that visfatin also participates in the osteoclasts’ formation by inhibiting osteoclastogenesis [89]. 5.

Resistin

Resistin, also called adipocyte-secreted factor are found in inflammatory zone 3 (FIZZ3), was discovered in 2001 and is a 12.5 kDa protein, which is constituted by 108 amino acids in human and 114 amino acids in mice. Resistin belongs to FIZZ family (also known as resistin-like molecules) [90,91]. The gene that codes for human resistin is located on chromosome 19p13.2. Mouse and human resistin genomic DNA have 46.7% similarity, and the proteins are 59% [91]. The major source of resistin in mice is WAT [90], whereas in humans, it is predominantly expressed in macrophages [92]. Thus, in human adipose tissue, resistin is mainly produced by non-adipocyte-resident inflammatory cells [93]. Resistin levels are elevated in animal models of obesity [90]. In addition, hyperresistinemia led to an increase in insulin insensitivity and impairment of glucose metabolism [94,95]. On the contrary, a reduction of resistin concentration improved insulin sensitivity and glucose homeostasis [96]. Thus, pharmacological observations clearly suggest that resistin plays a role in insulin resistance in rodents, but in humans the relation between insulin resistance and resistin is less clear [97]. Interestingly, resistin is associated with inflammation. Inflammatory stimuli induce resistin expression in different cell types [98]. Moreover, the induction of an experimental endotoxemia in humans results in a dramatic increase in resistin serum levels [99]. Resistin acts as a circulating polypeptide and it participates in many different processes. Multiple tissues have been described to be responsive to resistin and the mechanism of action might be both endocrine and paracrine but the resistin 950

receptor still remains unidentified. Intriguingly, a recent study demonstrated that resistin could bind and signal through Toll-like receptor 4 (TLR4) [100] through which cytokine production was triggered in peripheral blood mononuclear cells in response to resistin stimulation [100]. There is published evidence to support activation of both TLR4-dependent and -independent signaling pathways by resistin. For instance, resistin antagonizes insulin action in human and mouse adipocytes and the cellular mediator responsible for this mechanism seems to be mediated by SOCS-3 [101]. In the same way, resistin also modulates inflammation in human endothelial cells, through upregulation of SOCS-3, and the participation of STAT3 transcription factor is necessary for this purpose [102]. To note, resistin downregulate the activation of AMPK in rodent skeletal muscle, liver and adipose tissue [95]. Notably, the activation of NF-kB and C/enhancer binding protein b are involved in the upregulation of several cytokines and chemokines in response to this adipokine in chondrocytes [82]. Resistin and bone Resistin expression has also been reported in osteoblasts and osteoclasts [103]. The production of this adipokine increases during osteoclasts differentiation. Recombinant mouse resistin stimulates osteoclasts differentiation and osteoblasts proliferation [103]. These results suggest that resistin could contribute to bone metabolism and remodeling via two main ways: enhancement of osteoclasts differentiation and the recruitment of osteoblasts. Although certain studies showed that resistin is not associated with BMD [81,82,104], other groups found that resistin serum levels were negatively correlated with lumbar spine BMD [105]. In addition, in older patients with hip fracture, higher concentrations of resistin were also associated with cervical hip fracture [106]. Recently, a significant negative relationship between resistin and BMD of the femoral neck has been reported, although the correlation between resistin and lumber BMD was not significant [107]. Very recently, it has been reported that resistin is inversely correlated with osteocalcin in patients with osteoporotic hip fracture [40]. These observations suggest a crosstalk between resistin and osteocalcin, and this may be part of a complex regulatory system of bone and energy metabolism. The influence of resistin is still unclear, probably due to the fewer studies performed in order to ascertain the involvement of this adipokine in the pathogenesis of osteoporosis. Further studies are needed to clarify the function of resistin in modulating the bone microenvironment. 5.1

6.

Adipokines and fracture risk

Barbour et al. reported an association between adiponectin levels and increased risk of fracture, independent of BMI, diabetes, weight change and BMD in older men. However,




this association was not observed in older women. In contrast to adiponectin, no evidence of an association between serum leptin levels and risk of fracture in older adults was found [108]. A recent work of Johansson et al. confirmed a positive relationship between adiponectin and fracture risk in elderly men in Sweden, suggesting a possible role of this adipokine as a risk factor for increased fracture risk in men [109]. No data exist about the relationship between other adipokines and fracture risk, so that, more research is needed to evaluate this aspect. 7.

Other adipokines

Lipocalin-2 Lipocalin-2 (LCN2), also known as siderocalin, 24p3, uterocalin and neutrophil gelatinase-associated lipocalin (NGAL), is constitutively expressed in myelocytes and stored in neutrophil-specific granules [110,111]. LCN2 expression was also found in chondrocytes [112], although WAT is thought to be the main source [113]. NGAL can exist as a monomer, as a disulfide-linked homodimer or as a disulfide-linked heterodimer in a complex with MMP-9 [114,115]. Human NGAL consists of a single disulfide-bridged polypeptide chain of 178 amino acid residues with a calculated molecular weight of 22 kDa. The molecular weight of NGAL increases to 25 kDa, when the molecule is glycosylated [116]. LCN2 is involved in a series of processes such as apoptosis of hematopoietic cells [117], transport of fatty acids and iron [118] and modulation of inflammation [119]. It was shown that LCN2 binds iron and delivers it to the cells through a small molecular weight siderophore [120,121]. Particularly, LCN2 recognized a transmembrane receptor, recently cloned and named megalin (GP330), which is internalized in the cell by endocytosis [122,123]. LCN2 synthesis has been described in bone [124]. Recently, Costa et al. reported that NGAL could modulate the bone marrow microenvironment by increasing the expression of one of the most important bone niche factors, the stromalderived factor 1, a chemokine involved in the recruitment of hematopoietic precursors and playing a major role both in tissue repair and in the maintenance of the bone marrow microenvironment [125]. The same group reported that LCN2 expression increased during osteoblast differentiation, and what is more interesting is that the transgenic mice overexpressing LCN2 presented bone microarchitectural changes [126]; specifically, this transgenic mice showed reduced trabecular number and bone mass, growth plate alterations, decreased bone formation rate and higher bone resorption [126]. Further studies are needed to clarify the function of LCN2 in modulating the bone microenvironment. 7.1

Chemerin Chemerin, also known as tazarotene-induced gene 2 and retinoic acid receptor responder 2, is an adipokine with chemoattractant activity [127]. It is secreted as an 18 kDa inactive 7.2

proprotein and is activated by post-translational C-terminal cleavage [127]. Chemerin acts via the G-protein-coupled receptor chemokine-like receptor 1 (CMKLR1 or ChemR23) [127]. CMKLR1 gene was first cloned in 1996 as a gene encoding a putative 371 amino acid receptor containing seven transmembrane domains [128]. The downstream signaling involves different pathways, including ERK1/2 and Akt pathways [129]. Chemerin and its receptor are mainly, but not exclusively, expressed in adipose tissue [130], and, for instance, dendritic cells and macrophages express chemerin receptor [131]. Chemerin is also expressed in preosteoblastic cells and it seems to be involved in osteoblast differentiation [132]. Moreover, very recently, it was demonstrated that chemerin neutralization blocked osteoclast differentiation of hematopoietic stem cells [133]. Apelin Apelin is a peptide, recently identified as the ligand of the orphan G-protein-coupled receptor APJ [134]. Several active apelin forms exist such as apelin-36, apelin-17, apelin-13 and pyroglutamated form of apelin-13. Apelin has been detected in adipose tissue and is secreted by adipocytes [134,135]. Available data suggest that this adipokine could regulate bone metabolism. Although, there is one study showing that apelin did not represent an independent predictor of BMD [82], other authors reported that this adipokine had a positive effect on fetal/neonatal bone metabolism [87]. Another recent study demonstrates an increase in bone mass in mice lacking apelin [136]; in fact, these animals presented increased rates of bone formation and accelerated osteoblast formation and differentiation [136]. 7.3

Vaspin Vaspin is a serpin (serine protease inhibitor) that is produced in the visceral adipose tissue [137]. Human vaspin gene contains 1245 nucleotides encoding a putative protein with 415 amino acids [137]. It has been reported that vaspin attenuates RANKLinduced osteoclastogenesis in RAW264.7 cell line [138] and serum deprivation apoptosis in human osteoblasts [139]. 7.4

8.

Conclusion

In this review we have summarized the most relevant data regarding the interplay between certain adipokines and bone metabolism and diseases (Table 1). In the past years, many in vitro studies demonstrated the implication of the adipose tissue-derived factors described above in bone physiology. Moreover, clinical data revealed a potential involvement of adipokines in patients affected by bone diseases. However, the presence of some conflicting and unclear results makes it necessary for further research to better understand the regulation of bone metabolism by adipokines.


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Table 1. Summary of the main effects of adipokines on bone metabolism. Preclinical data

Clinical data

Leptin

--In vivo and in vitro studies reported both positive and negative effects of leptin on bone mass in a direct or indirect manner --SOCS-3 KO mice (with a partial gain of function in leptin signaling) show normal appetite control but an osteoporotic phenotype -Leptin negatively correlates with TrBD and positively with CtCSA in mice fed with a high-fat diet compared with age-matched normal diet control mice

--BMD was higher in obese adolescents and associated with higher serum leptin concentrations --LEPR c.1968G>C polymorphism may be one of the genetic factors affecting femoral neck BMD in postmenopausal Korean woman --Leptin might modulate a series of genes (alkaline phosphatase and osteocalcin) implicated in ossification, resorption and osteoblast differentiation

Adiponectin

--Mice treated with adiponectin showed increased trabecular bone mass and decreased number of osteoclasts --Adiponectin KO mice display increased bone mass

--An inverse relationship between adiponectin plasma concentration and total body BMD exists in adult men and women --Adiponectin levels has been associated with vertebral fractures in men with type 2 diabetes --The relationship between adiponectin and BMD depends on ethnicity

Visfatin

--Visfatin influences cell proliferation, glucose uptake and collagen type I synthesis in osteoblasts --Visfatin knockdown inhibits osteoclast formation

--Any clear correlation exists between visfatin and BMD

--Visfatin participates in the osteoclasts formation by inhibiting osteoclastogenesis --Visfatin exerts positive effects on fetal/neonatal bone metabolism Resistin

--Resistin production increases during osteoclasts differentiation --Recombinant resistin stimulates osteoclasts differentiation and osteoblasts proliferation in mouse

--Resistin serum negatively correlate with lumbar spine BMD --Higher concentrations of resistin are associated with cervical hip fracture in older patients --Significant negative relationship between resistin and BMD of femoral neck exists

New adipokines

Lipocalin-2 modulates bone marrow microenvironment by increasing the expression of SDF-1, and the expression of this adipokine increases during osteoblast differentiation --Chemerin neutralization blocks osteoclast differentiation of hematopoietic stem cells --Apelin presents a positive effect on fetal/neonatal bone metabolism --Vaspin attenuates RANKL-inducing osteoclastogenesis in RAW264.7 cell line

BMD: Bone mineral density; CtCSA: Cortical bone cross-sectional area; KO: Knockout; SDF-1: Stromal-derived factor 1; SOCS-3: Suppressor of cytokine signaling-3; TrBD: Trabecular bone density.

9.

Expert opinion

Patients affected by bone diseases present an altered adipokine profile, which could be used as powerful marker/s in the search of novel therapies. We have highlighted several pieces of data which demonstrated the involvement of adipokines in bone cells differentiation and bone metabolism. Most of the articles reviewed herein have revealed a putative role of adipokines in the development of bone diseases. In vitro, in vivo and clinical studies have shown a clear implication of these family proteins in certain processes that regulates BMD. However, it is currently too soon to define a 952

therapeutic strategy using adipokines, due to the incomplete knowledge about the specific way of action of these proteins and the presence of controversial results. For future progression, the first step needed, in the search of new therapeutic goals for bone diseases, would be a deeper and complete understanding of the mechanism of action of adipokines at bone level. In recent times, researchers have tried to explain how some factors secreted by adipose tissue can influence bone metabolism and participate in the onset and progression of osteoporosis. Indeed, recently published articles related with this topic have increased in the last years and there is no doubt




that this number will increase in the coming years. Both basic and clinical research will be essential to completely understand the degree of involvement of adipokines in bone-related pathologies. It should be noted that although many of the aspects of the interaction between adipokines and bone metabolism remain unclear and incomplete, several therapeutic suggestions have been founded. For instance, the possibility to antagonize adipokine actions, in a similar way that TNF-a blockers are used in chronic autoimmune diseases like rheumatoid arthritis by using high-affinity adipokine-binding molecules or by blocking certain receptors with monoclonal humanized antibodies, is likely feasible. However, the complexity of adipokine system highlights the question of if it may be possible to selectively target the mechanism/s by which these molecules contribute to bone disease without suppressing their normal physiological actions. The strongest evidence emphasized in this review indicates the rapid and substantial advancement in our understanding of the interplay between bone metabolism and the metabolic system. With these insights, it may be possible to develop new treatment strategies and interventions with the aim of successful outcomes for the many people affected by bone disorders. Certainly, further insights into the intimate mechanisms regulating peripheral and central activity of adipokines might be a great advantage for functional pharmacotherapeutic approaches with bone diseases. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

..

2.

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Acknowledgment M Scotece and J Conde have contributed equally to the realization of this work.

Declaration of interest The work of O Gualillo and F Lago is funded by Xunta de Galicia (SERGAS) through a research-staff stabilization contract. O Gualillo is supported by Instituto de Salud Carlos III and Xunta de Galicia (grants PI11/01073 and 10CSA918029PR). O Gualillo’s work was also partially supported by the RETICS Programme, RD08/0075 (RIER) via Instituto de Salud Carlos III (ISCIII), within the VI NP of R+D+I 2008-2011. M Scotece is a recipient of the ‘FPU’ program of the Spanish Ministry of Education. J Conde is a recipient of a fellowship from the Foundation IDIS-Ramoń Dominguez. V Lopez is a recipient of a grant from Instituto de Salud Carlos III. V Abella is a recipient of a predoctoral from European Social Fund grant from Xunta de Galicia through a contract signed with University of Corunã. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Morena Scotece1, Javier Conde1, Vanessa Abella1,2,3,4,5, Verońica Lo´pez1, Jes us Pino2, Francisca Lago3, Juan J Go´mez-Reino4 & Oreste Gualillo†1 † Author for correspondence 1 Santiago University Clinical Hospital, SERGAS, Division of Rheumatology, Research Laboratory 9, Santiago de Compostela, 15706, Spain E-mail: [email protected] 2 Santiago University Clinical Hospital, SERGAS, Orthopaedic Surgery, Santiago de Compostela, 15706, Spain 3 Santiago University Clinical Hospital, SERGAS, Research Laboratory 7, Santiago de Compostela, 15706, Spain 4 Santiago University Clinical Hospital, SERGAS, Rheumatology Division, Santiago de Compostela, 15706, Spain 5 University of A Corunã, A Corunã, Spain

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MicroRNAs regulate bone metabolism.

Bone anabolics in osteoporosis: Actuality and perspectives.

Chemical kinetics for drug discovery to combat protein aggregation diseases.

Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila.