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Keywords:

  • aging;
  • bone;
  • fat;
  • obesity;
  • osteoporosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

Kawai M, de Paula FJA, Rosen CJ (Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan; University of São Paulo, Ribeirão Preto, SP, Brazil; and Maine Medical Center Research Institute, Scarborough, ME, USA). New insights into osteoporosis: the bone–fat connection (Review). J Intern Med 2012; 272: 317–329.

Abstract.  Osteoporosis and obesity are chronic disorders that are both increasing in prevalence. The pathophysiology of these conditions is multifactorial and includes genetic, environmental and hormonal determinants. Although it has long been considered that these are distinct disorders rarely found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. It is proposed that adiposity may influence bone remodelling through three mechanisms: (i) secretion of cytokines that directly target bone, (ii) production of adipokines that influence the central nervous system thereby changing sympathetic impulses to bone and (iii) paracrine influences on adjacent skeletal cells. Here we focus on the current understanding of bone–fat interactions and the clinical implications of recent studies linking obesity to osteoporosis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

Recent advances in our understanding of the mechanisms that maintain skeletal homoeostasis have highlighted the possibility that bone metabolism may be integrated with multiple organ systems including the network of adipose tissue. Three possible mechanisms may underlie the effects of adiposity on skeletal turnover: (i) endocrine cytokines and growth factors released by adipocytes affect osteoblasts and osteoclasts; (ii) adipokines (e.g. leptin and adiponectin) regulate central nervous system outflow from the sympathetic nervous system; and (iii) paracrine factors secreted by adipocytes within the bone marrow milieu influence nearby cells on the trabecular bone surface.

First, with regard to the endocrine mediation of adipose tissue, visceral fat depots with an inflammatory element secrete cytokines, including resistin, tumour necrosis factor-α (TNF-α), interleukin (IL)-1 and IL-6, which uncouple bone remodelling by enhancing bone resorption or suppressing bone formation. Secondly, leptin and adiponectin can similarly influence bone remodelling by endocrine actions or through their influence on hypothalamic centres that regulate sympathetic tone. The outflow of sympathetic impulses inhibits osteoblast differentiation and enhances osteoclast recruitment thereby uncoupling the bone remodelling unit. Thirdly, regarding the paracrine actions of adipose tissue, bone marrow adipocytes, first identified more than a century ago, are an essential part of the bone marrow microenvironment and are clearly integral to both skeletal function and haematopoiesis. Moreover, the differentiation programmes of osteoblasts and adipocytes share a common ancestor, the mesenchymal stem cells (MSCs). Thus, a new perspective about bone–fat interactions has emerged, particularly regarding skeletal metabolism.

In this review, we will focus on current knowledge of the interaction between adipose tissue and the skeleton and, in particular, on the shared hormonal modulators and paracrine effects of bone marrow adiposity on skeletal remodelling.

Hormonal interactions between bone and fat

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

With the recent rise in obesity worldwide and the consequent increased interest in the pathophysiology of this condition, adipose tissue, long considered to be an inert site for energy storage, has emerged as an endocrine modulator of satiety, energy balance and pubertal development [1, 2]. Furthermore, disorders of adipose tissue function have recently been linked to common chronic diseases such as atherosclerosis, diabetes mellitus and osteoporosis [3–6].

Adipose tissue is characterized by an abundance of adipocytes and a stromal vascular fraction that contains bipotent stem cells, which can differentiate into adult adipocytes or, under the appropriate conditions, pre-osteoblasts. Adipocytes have a specialized function to store fatty acids as triglycerides for future use as substrates for energy utilization. In addition, these cells secrete peptides (i.e. adipokines) that influence whole-body metabolic homoeostasis via autocrine, paracrine and endocrine pathways. Adipocytes are regulated by multiple factors including the number of precursor cells, total substrate availability and hormonal influences. With respect to the latter, insulin is a critical determinant of adipocyte function by stimulating glucose uptake and inhibiting lipolysis. Insulin also enhances adipocyte differentiation and determines both adipose tissue expansion and retraction in response to nutrient availability. It is not surprising that disorders of insulin secretion and resistance (including both type I and type II diabetes), with either high or low levels of circulating insulin, have been associated with changes in adipocyte structure and function. Of note, insulin receptors are also found on osteoblasts and, through their presence, insulin can promote osteoblast differentiation. In a genetic model of conditional deletion of insulin receptors in bone, Fulzele et al. [7] observed a decrease in bone mass and a metabolic phenotype including insulin resistance and increased body fat. Taken together, it appears that there is a close relationship between adipocytes and osteoblasts both structurally and functionally.

Amongst the adipokines released by adipocytes, leptin has one of the most important roles in metabolic homoeostasis. Leptin acts by binding to the leptin receptor (LRb), which in turn triggers phosphorylation of cytoplasmic tyrosine residues of LRb that mediate various signalling pathways including the JAK2-STAT3, Erk1/2 and PI3K pathways [8, 9]. Leptin regulates body weight by modulating receptor-expressing neurons in the central nervous system, particularly within the hypothalamus and brainstem [8, 10]. However, leptin has pleiotropic metabolic effects, controlling energy expenditure, locomotor activity, feeding behaviour, fertility, bone mass, linear growth, adrenal activity and life span. Thus, mice with congenital absence of leptin (ob/ob mice) or the leptin receptor, LRb, (db/db mice) exhibit a complex phenotype with abnormalities in several organ systems. In particular, these mice are obese but, in spite of their hormonal profile (i.e. hypogonadism and increased glucocorticoid levels), have high bone mass [11]. Because leptin evolved coincident with the appearance of vertebrates, it has been hypothesized that the skeleton is a major leptin target [12]. Supporting this hypothesis, it has been observed that mice harbouring a mutation that leads to a partial gain of function in leptin signalling exhibit normal appetite, but an osteoporotic phenotype [13, 14].

Most but not all [15] evidence suggests that leptin acts centrally to inhibit the accumulation of bone mass [12]. One of the most convincing arguments in favour of this suggestion is that a neuron-specific deletion of Lepr induces the bone phenotype of ob/ob mice, whereas an osteoblast-specific deletion has no such effect [12, 15]. Moreover, the skeletal phenotype of ob/ob mice can be corrected by leptin administration into the third ventricle [11]. The pattern of bone changes in leptin-deficient mice may be reproduced by chemical lesioning of neurons in the ventromedial hypothalamus [16]. This neural damage also prevents the skeletal changes that result from central administration of leptin. Thus, emerging evidence suggests that the hypothalamic ventromedial nucleus is the key site in the central nervous system for leptin regulation of bone mass [16]. From this nucleus, sympathetic fibres transmit stimuli to bone via osteoblasts, which express an abundance of the β2 adrenergic receptor (β2 AR) [16]. Support for this suggestion comes from genetically engineered β2 AR-knockout mice that have the same bone phenotype as ob/ob mice and animals with chemical injury to the ventromedial nucleus. It was recently demonstrated that the leptin receptor, LRb, in hypothalamic ventromedial neurons is not necessary to trigger the action of leptin [17]. These data indicate that leptin probably acts at other sites in the brain to regulate metabolism. Serotonergic neurons of the brainstem are reasonable candidates as mediators of this action, because the consequences of leptin deficiency for bone turnover and metabolism can be reversed by suppressing serotonin production in the brainstem [18]. In summary, the adipokine leptin plays a critical role not only in regulating appetite, reproductive capacity and energy consumption but also in bone turnover through its actions on the central nervous system.

Bone and metabolic disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

Adipose tissue, which under normal conditions shows a high level of insulin sensitivity, is a source of insulin resistance [19, 20]. The metabolic manifestations of insulin resistance include changes in the levels of several adipokines, attraction of inflammatory macrophages and alterations in tissue remodelling and lipolytic activity [20, 21]. The hyperinsulinaemia that results from physiological compensation also affects ‘off target’ tissues [22–25]. Off target sites such as the vasculature and gonadal production include two major phenotypes: hyperandrogenism and hypertension [22, 23, 26]. However, the impact of insulin resistance on bone cell function is still under investigation using both genetic models and human studies.

Notwithstanding the difficulty in defining the role of insulin resistance in skeletal remodelling, the physiological interplay between bone and insulin has been established through recent investigations. The osteoblast is an insulin-sensitive cell which, as mentioned earlier, expresses the insulin receptor [7]. Genetically engineered mice lacking the insulin receptor in osteoblasts show a decrease in bone formation but, remarkably, these animals also have increased body fat and impaired insulin sensitivity (Fig. 1). These findings prompted investigators to postulate that there was a bone-specific protein modulating energy metabolism. Synthesis of osteocalcin, the most abundant noncollagen peptide in the skeletal matrix, is modulated at least in part by insulin. Osteocalcin is carboxylated post-translationally on three glutamic acid residues in a vitamin K-dependent manner by the enzyme γ-carboxylase [27]. The product, the amino acid γ-carboxyglutamic acid, has the capacity to bind to calcium. On the other hand, decarboxylation decreases the hydroxyapatite-binding affinity of osteocalcin. Undercarboxylated osteocalcin that enters the circulation regulates energy metabolism, through increases in β-cell proliferation, insulin secretion and insulin sensitivity [7, 28, 29]. Lee et al. [29] provided the first evidence of this role, the role of osteocalcin carboxylation in metabolic homoeostasis, by the identification of the ESP gene, which encodes the intracellular protein tyrosine phosphate (OST-PTP in mice; PTP1B in humans) involved in the carboxylation of osteocalcin.

An endocrine connection between bone and pancreas, where insulin promotes osteocalcin synthesis and osteocalcin in turn leads to enhanced insulin secretion, establishes a somewhat atypical feed-forward loop (see Fig. 1 [12]). Additionally, there is evidence that the osteoclast has a role in this process; insulin signalling in osteoblasts inhibits the expression of osteoprotegerin, allowing receptor activator of nuclear factor–κB ligand to stimulate bone resorption by osteoclasts. The acidic microenvironment created by these multinucleated cells favours the decarboxylation of osteocalcin [28]. It is likely that undercarboxylated osteocalcin has a greater capacity than carboxylated osteocalcin for stimulating β-cell proliferation and insulin secretion [30]. It is interesting that animals lacking the insulin receptor in classic target tissues (i.e. muscle or adipocytes) do not show glucose intolerance, suggesting that other sites, such as the skeleton, are engaged in the control of glucose disposal.

image

Figure 1. Insulin regulates skeletal homoeostasis. Insulin regulates skeletal homoeostasis in part by stimulating new bone formation and bone remodelling. Insulin deficiency or resistance leads to reduced bone mass and increased skeletal fragility. Enhanced bone resorption increases release of undercarboxylated osteocalcin, which in turn can enhance insulin secretion and adipocyte sensitivity [7].

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Further support for the idea that bone is integrated with metabolic homoeostasis comes from clinical and experimental studies. Insulinopenic states such as in human type 1 diabetes [31, 32] and pharmacologically induced diabetes [33] are clearly associated with decreased bone mass and skeletal fragility. In both cases, low serum levels of osteocalcin or decreased osteocalcin expression in bone reflect impaired bone formation and a fundamental defect in osteoblast function during states of insulin deficiency. As noted, additional evidence of bone regulation by insulin has been acquired through specific genetic deletion of insulin receptors in osteoblasts [7]. Insulin receptor silencing resulted in low bone mass and was associated with increased expression of Twist2 and decreased expression of osteocalcin and Runx2. The transcriptional factor Twist2 acts as a cellular inhibitor of Runx2; the latter is a key determinant of osteoblast differentiation. Therefore, a multitude of factors lead to bone loss and ultimately to bone fragility in type 1 diabetes mellitus [34, 35].

Obesity is associated with several major health problems and has a strong psychological impact on the individual. Hypertension, diabetes mellitus and dyslipidaemia, the classic triad of conditions associated with insulin resistance, are also all closely associated with obesity and together increase significantly the risk of cardiovascular disease [36]. Recent evidence suggests that, independent of weight, glucose intolerance in those with hypertension, diabetes mellitus and dyslipidaemia, is associated with greater skeletal fragility despite near normal bone mineral density (BMD). Moreover, ultrastructural analysis of skeletal morphology in patients with insulin resistant diabetes suggests that there is an increase in cortical porosity which may be a major contributor to the heightened fracture risk often observed in these patients. Moderate weight loss is an efficient way to prevent the risk of developing diabetes mellitus in overweight and obese individuals [37], whilst drastic weight loss enhances the life expectancy of severely obese patients. Thus, weight loss should be encouraged to decrease the risk of cardiovascular disease and related disorders. However, hard tissue seems to be exquisitely sensitive to rapid reductions in body weight. For example, weight loss induced by bariatric surgery, despite the improvement in insulin sensitivity and overall health, is associated with significant bone loss [38, 39]. Long-term studies are required to determine whether this loss in bone mass is reversible with sustained weight loss and changes in anthropomorphic indices.

It is not surprising that low body weight is also associated with changes in skeletal remodelling. Nutritional restriction in mice [40] and anorexia nervosa in humans are established causes of osteoporosis [41]. Insulin sensitivity was recently investigated in patients with anorexia nervosa. The lack of adipose tissue in lipodystrophy is accompanied by insulin resistance, therefore Karczewska-Kupczewska et al. [42] evaluated insulin sensitivity by measuring glucose disposal and serum adiponectin concentration in women with anorexia nervosa. There are three forms of insulin-sensitizing factor adiponectin, and all were found to be increased in anorexic patients. In a similar study, Ecklund et al. [43] showed that, in parallel to both bone and fat depot loss, anorexic patients had increased adiposity in the bone marrow niche that paralleled the increase in adiponectin and the heightened insulin sensitivity. Consistent with these findings, it was recently shown that preadipocyte factor-1 (Pref-1) levels are increased in the circulation of anorexic women as is another insulin-sensitizing factor Fibroblast growth factor-21, FGF-21 [44, 45]. Pref-1 is a member of the epidermal growth factor-like family of proteins and a suppressor of both adipocyte and osteoblast differentiation. Moreover, a positive correlation was observed between circulating concentrations of Pref-1 and marrow fat in the proximal femur of all women in the study by Karczewska-Kupczewska et al.

The association between insulin sensitivity/resistance and bone remodelling is a critical determinant when considering future strategies for the therapy of type II diabetes mellitus. Thiazolidenediones (TZDs), a class of exogenous agonists of peroxisome proliferator-activated receptor-γ (PPAR-γ), were introduced for the treatment of type II diabetes mellitus one decade ago [46]. PPAR-γ exists in two major forms, PPAR-γ1 and PPAR-γ2. PPARγ 1 is expressed in a large range of tissues, including the liver, skeletal muscle, adipose tissue and haematopoietic cells. The expression of PPARγ 2, which contains 30 additional amino acids at the N-terminal, is primarily restricted to adipocytes, stromal cells and osteoblasts. TZDs have a complex and incompletely understood mechanism of action. The improvement in glucose metabolism is partly due to their influence on endocrine factors in adipose tissue, but they also have independent metabolic effects. TZDs stimulate the maturation of visceral fat, and hence change the adipocytokine profile of adipose tissue. These agents lead to an increase in adiponectin levels, which counterbalance the effects of proinflammatory cytokines such as TNF-α and promote beta oxidation of fatty acids via the activation of 5′adenosine monophosphate-activated protein kinase (AMP-K) [47]. The increase in beta oxidation, together with a reduction in de novo lipogenesis, reduces gluconeogenesis [48].

In the ADOPT trial, which was designed to investigate the long-term efficacy of metformin, glyburide and rosiglitazone for the treatment of type II diabetes mellitus, an increased risk of fracture was detected in women, but not in men, treated with rosiglitazone compared to women treated in the other study arms [49]. Similar results with pioglitazone were also reported in a note by Eli Lilly Canada Inc. Grey et al. [50] reported the results of a 14-week randomized clinical trial comparing rosiglitazone (8 mg day−1) to placebo in 50 postmenopausal women with normal glucose tolerance. In the rosiglitazone group, the decline in biochemical markers of bone formation (osteocalcin and procollagen type 1 N-telopeptide) was of the order of 10–12% compared to placebo. There was no change in serum C-telopeptide, β-CTX, a marker of bone resorption. These changes in bone turnover were accompanied by a significant 2% decline in total BMD in the rosiglitazone-treated group, even within the short time frame of this trial.

Taken together, hormonal determinants of adipose tissue can have a profound effect on skeletal remodelling. Energy availability, which is sensed by cells that produce these circulating hormonal factors, almost certainly plays a major role in determining how the skeleton responds to bone remodelling. In part, the cellular mechanisms mediating these skeletal changes can be traced to the bone marrow where multipotent stem cells undergo lineage allocation to either the adipocytic or osteogenic programme. These cells ultimately determine the relationship between bone and fat.

Role of marrow adipocytes in skeletal metabolism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

Transcriptional network of adipogenesis: marrow adiposity

The molecular mechanisms of adipocyte differentiation have been studied using both in vitro and in vivo models. A number of growth factors have been found to have a role including insulin-like growth factor 1 (IGF-I), growth hormone and insulin, emphasizing the critical connection between nutrient status and the development of adipose tissue. Adipose tissue formation is defined by integrated steps of adipocyte differentiation and maturation. These steps have been intensively studied, and multiple transcription factors have been found to be involved.

The initial step of adipogenesis involves the lineage commitment of MSCs into preadipocytes, followed by the expansion of these cells. These preadipocytes in the stromal vascular fraction of adipose depots undergo a differentiation programme under the tight control of multiple transcription factors including C/EBPβ and δ and PPARγ. The transcription factor and nuclear receptor PPARγ plays a central role in adipogenesis as evidenced by the fact that loss of Pparg in mouse embryonic fibroblasts leads to a complete absence of adipogenic capacity [51]. In vitro, multiple transcription factors and co-regulators have been shown to modulate the expression and function of PPARγ. For example, differentiation of 3T3-L1 cells, a well-recognized cell line that is used as a model of adipogenesis in vitro, is regulated by the integration of several transcription factors including C/EBPβ and δ. These factors stimulate Pparg transcription by directly binding to the promoter region [52]. Increased expression of Pparg activates the expression of another member of the C/EBP family, C/EBPα, which in turn enhances the expression of PPARγ. Partial loss of function of C/EBPα results in a mouse (A-Zip) with very little adipose tissue, including almost none in the bone marrow, but increased bone mass. Thus, the C/EBP family is critical for the induction of PPARγin vitro. However, adipogenesis in vivo is complex and requires other transcriptional and co-factors for PPARγ regulation in part because, as demonstrated by the A-Zip mouse, PPARγ expression is maintained in the adipose tissue of mice lacking C/EBPβ and/or δ [53].

It is likely that the transcriptional network of marrow adipogenesis is governed by the same mechanisms used to regulate white adiopocyte differentiation, and PPARγ is certainly critical in this process For example, streptozotocin-induced type 1 diabetic mice exhibit massive infiltration of marrow adiposity, which is antagonized by treatment with the PPARγ antagonist bisphenol A diglycidyl ether (BADGE) [54]. Consistent with this finding, BADGE also suppresses marrow adipogenesis induced by irradiation in mice [55]. Similarly, marrow adiposity is induced by treatment with PPARγ agonists (TZDs), although this effect is quite variable and dependent on the type of TZD, further supporting the critical role of PPARγ in marrow fat generation.

Regulation of marrow stromal cell fate by PPARγ: implications for the development of osteoporosis

It is well recognized that adipogenesis is tightly linked to osteogenesis in the bone marrow milieu, as demonstrated by the finding that osteoblasts and adipocytes share a common precursor (i.e. the MSC) [56–58]. Determination of MSC fate towards either adipocytes or osteoblasts is a fine-tuned process, and a number of lineage-specific transcription factors (such as Runx2 and osterix for osteoblasts, and PPARγ2 for adipocytes) have been shown to be involved [59–62]. It is interesting that suppression of PPARγ stimulates osteoblastogenesis and enhancement of PPARγ activity results in decreased osteogenesis, suggesting an inverse correlation between osteogenesis and adipogenesis [63]. These observations are also consistent with findings in a mouse model of ageing in which marrow adiposity was increased, bone mass was reduced and PPARγ2 expression was enhanced [64]. Similarly, haploinsufficiency or a hypomorphic mutation of Pparg has been reported to increase bone mass and reduce marrow adiposity associated with an increase in osteoblast number and bone formation [65, 66]. Because PPARγ expression in the bone marrow increases with age, it is conceivable that PPARγ activation in the bone marrow is at least in part responsible for the age-related decrease in bone mass and increase in marrow adiposity. However, the hypothesis of lineage allocation has recently been challenged by the findings from several groups that enhanced osteoblast activity can be found in the marrow of mice with marrow adiposity.

In addition to the pivotal role of PPARγ in lineage allocation of MSCs, mounting evidence indicates that PPARγ is involved in osteoclast differentiation. For example, PPARγ activation has been shown to activate bone resorption in part through enhancing osteoclast differentiation by recruitment of another co-activator of PPARγ, PGC-1beta [67–70]. Furthermore, the effect of PPARγ activation on osteoclastogenesis could be mediated in part by the increased expression of Rankl in an age-dependent manner [71]; however, the exact role of PPARγ in osteoclastogenesis still needs to be fully defined [72, 73]. Taken together, several lines of evidence highlight the pivotal role of PPARγ in the regulation of osteogenesis, adipogenesis and osteoclastogenesis, which could all contribute to the pathogenesis of osteoporosis.

Development of marrow fat in humans

Development of marrow fat in humans is age- and context specific. There is no marrow fat at any site in newborn infants; marrow at all skeletal sites is principally haematopoietic. However, adipocyte number increases with age, particularly in the appendicular skeleton, so that most of the femoral marrow cavity is occupied by adipose tissue in individuals older than 30 years of age. Indeed, recent studies have indicated that more than 70% of the marrow space is occupied by fat in the appendicular skeleton of adults. This age-related increase in marrow adiposity has been associated with age-related bone loss and BMD, establishing the widely accepted view of an inverse correlation between these parameters. Whilst this relationship may hold in pathological conditions (including postmenopausal osteoporosis), with drug use (e.g. corticosteroids and TZDs), and during ageing and malnutrition, it may not do so under physiological conditions. For example, infiltration of marrow adipocytes occurs around the time of peak bone acquisition [74], supporting the hypothesis that marrow adipocytes may create a favourable skeletal microenvironment for osteoblastogenesis, thereby maximizing bone accrual during puberty. Similarly adipocyte infiltration precedes osteogenic differentiation and new bone formation during fracture repair (Fig. 2) and following radiation therapy before bone marrow transplantation.

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Figure 2. Schematic model of bone–fat connections. Leptin regulation of bone mass includes: (i) activation of sympathetic nervous system/β-adrenergic signalling through hypothalamic integration, which results in bone loss, and (ii) direct anabolic effects on osteoblasts. However, the precise mechanisms of leptin action on skeletal homoeostasis remain unknown. Osteocalcin produced by osteoblasts decreases fat mass in part through promoting adiponectin production in adipocytes, and activation of PPARγ has been shown to cause increased adipose tissue mass and bone loss. Secretory factors produced by adipocytes, such as imflammatory cytokines, fatty acids, leptin and adiponectin, can positively or negatively regulate skeletal mass. In the bone marrow milieu, marrow adipocytes play a pivotal role in the regulation of osteoblast function. Secretory factors including inflammatory cytokines are also produced by marrow adipocytes. These cytokines may act on osteoblasts in a paracrine manner and suppress osteoblast function and/or differentiation in pathogenic conditions, whereas marrow adipocytes may positively regulate bone mass under physiological conditions; however, this hypothesis needs to be verified. In addition, activation of PPARγ causes bone loss in part through altering the fate of MSCs towards adipogenesis and away from osteogenesis, resulting in a decrease in the osteoblast pool in the bone marrow microenvironment. SNS, sympathetic nervous system; PPAR, peroxisome proliferator-activated receptor; C/EBP, CCAAT/enhancer-binding protein; RUNX2: runt-related transcription factor, MSC: mesenchymal stem cell.

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The development of marrow adipocytes is strongly affected by nutritional status. Despite the similarities in terms of the transcriptional machinery used in the development of marrow adipocytes, the trigger for adipocyte formation could be different from that for white adipose tissue. In fact, marrow adipocyte infiltration is often observed in the clinical setting, referred to as ‘fat redistribution’, in which marrow fat infiltration is associated with a decrease in peripheral adipose depots. For example, HIV-related lipodystrophy causes a significant decrease in peripheral adipose tissue, whereas marrow adiposity is enhanced. Similarly, states of malnutrition including anorexia nervosa lead to an increase in marrow adiposity with concurrent peripheral loss of adipose depots. Of note, over-nutrition is not a contributor to the development of marrow adiposity, suggesting that the amount of peripheral fat is not correlated with marrow adiposity. In fact, in recent work by Di Iorgi and colleagues, adolescents and young adults had significant marrow adiposity in the appendicular skeleton, but this was not related to subcutaneous or visceral fat depots, or markers of cardiovascular risk [75]. There is also evidence of a positive correlation between vertebral marrow adiposity and visceral fat mass in some settings, suggesting that the relationship might be compartment specific [76].

The function of marrow fat

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

Physiology

The physiological role of adipocytes in human bone marrow is largely unknown. Marrow fat had long been regarded as a ‘filler’ for space remaining after trabecular bone loss, which is often seen in elderly people and patients with osteoporosis [77–80]. Marrow adipogenesis has thus been considered a default pathway in which MSCs enter the fat lineage because of their inability to differentiate into more complex cells such as osteoblasts or chondrocytes. However, with a considerable change our understanding of fat tissue as an endocrine organ, the possibility that marrow adipocytes possess similar metabolic characteristics to some brown fat depots has emerged. Moreover, the juxtaposition of adipose tissue within the bone marrow milieu suggests that its presence may have consequences for the skeleton, with a balanced bone marrow microenvironment including marrow adipocytes being essential for normal osteogenesis [58, 81]. Indeed, increased production of adipose-related factors, such as fatty acids, could affect metabolism in the bone marrow either positively or negatively depending on the nature of the fatty acid and the type of receptor activation on MSCs [82]. In addition, adipokines, steroids and cytokines [83–85] can exert profound effects on neighbouring marrow cells, sustaining haematopoietic and/or osteogenic processes [78, 80, 84, 85] (Fig. 2).

‘Brown-like’ characteristics of marrow fat

Expression profiling of marrow adipocytes in a strain of mouse with a high bone mass (C3H/HeJ) has revealed the expression of genes involved in thermogenesis (e.g. UCP1) and lipid metabolism, suggesting that marrow adipocytes could be metabolically active [86, 87] (Rosen, unpublished data). Furthermore, using nuclear magnetic resonance spectroscopy, it was revealed that the saturated/unsaturated fatty acid ratio in the bone marrow of C3H/HeJ mice was nearly identical to that observed in interscapular brown adipose tissue (BAT). Similarly mice treated with rosiglitazone have enhanced marrow adiposity with spectroscopic and genotypic characteristics identical to BAT. These observations indicate that marrow adipocytes may possess ‘brown-like’ characteristics.

‘Bright’ (brown-like) cells have recently been the focus of intense investigations particularly with regard to novel treatments for obesity as these cells generally have a role in thermogenesis rather than storage. These cells are found in multiple adipose depots and are activated by increased sympathetic tone. However, brown-like adipogenesis is site- and context specific. Pharmacological interventions to convert white adipose tissue to brown-like adipocytes are now being tested in animals; there are high expectations that ultimately obesity may be treatable with one of these agents. In the bone marrow, brown-like adipocytes could provide an energy source for neighbouring cells such as osteoblasts or may simply be a means of maintaining thermoneutrality in the marrow, particularly in the appendicular skeleton (Fig. 3).

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Figure 3. Function of marrow fat. Marrow adipocytes produce a number of secretory factors. Such factors could have a significant role in osteoblast differentiation and/or function. In pathogenic conditions, these determinants may have a negative impact on osteoblasts, but a different effect under physiological conditions. There is also evidence that marrow fat is metabolically active and that genes characteristic of brown adipocytes are expressed in marrow adipocytes.

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Implications for osteoporosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

Marrow fat and ageing

Ageing is one of the risk factors for the development of osteoporosis. Age-related bone loss is characterized by the uncoupling of the bone remodelling network in which bone formation is suppressed and is associated with enhanced bone resorption. The underlying mechanisms of age-related bone loss are extremely complex with multiple factors known to be involved. Accumulating evidence clearly demonstrates that age-related bone loss is associated with an increase in marrow adiposity [88]. In a cross-sectional study of post-mortem iliac crest biopsies, adipose tissue volume increased from 15% to 60% between the ages of 20 and 65 years, whilst trabecular bone volume decreased from 26% to 16% [89]. More recently, Justesen et al. [90] reported that marrow adipose tissue increased from 40% at 30 years of age to 68% at 100 years, with a marked decrease in bone volume.

Alteration of MSC commitment is also important in age-related bone loss. With ageing, stromal cells obtained from human bone marrow have been shown to exhibit an increased number of adipogenic cells coincident with a decline in the number of osteoblastic cells. This is in part explained by the enhanced expression of PPARγ in the bone marrow with ageing, thereby favouring adipogenesis of MSCs whilst suppressing osteogenesis. The decreased expression of growth factors involved in osteogenesis, such as TGF-β/BMP, Wnt/β-catenin and IGF-I, probably also causes a decrease in the number of osteoblasts with ageing [64]. In addition to the alteration in cell fate determination, phenotypic changes in MSCs with ageing could also be responsible for age-related bone loss. For example, impairment of cell proliferation and differentiation, as well as chromosomal instabilities of MSCs, has been demonstrated in long-term cell culture models [91].

Marrow fat and osteoporosis

It has been recognized that subjects with osteoporosis exhibit greater infiltration of marrow adipocytes than age-matched controls [89, 92]. In in vitro experiments, MSCs isolated from patients with osteoporosis showed enhanced adipogenic capacity either under basal conditions or during early cell differentiation, compared to cells from control subjects [56, 85, 93, 94]. This may be caused by a decrease in the proliferative capacity of MSCs of patients with osteoporosis, and an impaired mitogenic response to IGF-1 [94, 95]. The altered differentiation capacity of MSCs towards adipogenesis and away from osteogenesis could provide another level of regulation. For example, MSCs derived from donors with osteoporosis have reduced alkaline phosphatase activity and less mineralization when maintained in osteogenic conditions. In addition to the intrinsic characteristic of MSCs of cell commitment and differentiation, it is recognized that locally produced growth factors such as leptin, oestrogens and fatty acids may be involved in the regulation of osteoblastogenesis. For example, in vitro studies confirmed that bone marrow stromal cells were responsive to leptin; it was found that leptin stimulates osteoblastic differentiation of stromal cells [96–98] and suppresses adipogenesis of these cells [97, 99].

Endogenous oestrogens also play a crucial role in the development of marrow adiposity and bone loss. Not only does uncoupling of the bone remodelling units result from a decrease in oestrogen levels especially after the menopause, there is also a marked increase in marrow adiposity accompanied by a decline in bone mass [90, 100]. This is in part explained by the direct effect of oestrogen on the cell fate of MSCs towards either osteoblasts or adipocytes [101, 102]. Of note, regulation of aromatase activity may provide another level of regulation of bone mass by marrow adipocyets because aromatase is highly expressed in bone marrow stromal cells [103–108]. Hence, it is possible that locally produced androgens and oestrogens in marrow adipocytes can exert regulatory actions on bone marrow cells including osteogenic cells. Studies of MSC differentiation point to the potential importance of local oestrogen production and activity for osteogenic and adipogenic commitment [102, 103], and as a negative regulator for adipogenesis [109, 110]. All these observations support the hypothesis of a threshold oestrogen level for normal skeletal remodelling [111, 112], which could be reached by both appropriate endogenous aromatase activity and oestrogenic precursors.

Significance of marrow adiposity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

Attempts to determine the exact function of marrow adipocytes especially with respect to their influence on skeletal homoeostasis have encountered significant difficulties. Clearly, marrow adipocytes are critical components of the bone marrow microenvironment and affect the physiology of neighbouring cells including haematopoietic cells and osteoblasts. But to clarify the role of marrow adipocytes, it will be necessary to characterize the functional features of these cells. Currently available techniques including magnetic resonance imaging with and without spectroscopy, microcomputed tomography and histology are useful for quantifying the amount of marrow fat, but do not provide functional information about the type of adipocyte and its role in the marrow.

However, accumulating evidence from expression profiling has suggested that marrow adipocytes may function in a way similar to either white or brown adipocytes in a context-specific manner. This is extremely plausible because marrow adiposity is likely to have a dual effect on skeletal metabolism depending on age: bone mass and marrow adiposity both increase during puberty, whereas bone mass has an inverse correlation with marrow adiposity in the elderly. If marrow adipocytes have brown-like characteristics, it is conceivable that these cells create a favourable microenvironment for osteogenesis by functioning as a source of energy for osteogenesis or as a temperature modulator. Regardless of the mechanism, the consequences of marrow adiposity as it relates to structural integrity still need to be defined.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References

There is an intimate association between bone cells and adipocytes stemming from their shared origin. Important regulatory pathways in adult adipose tissue modulate skeletal remodelling as well as the direct effect of adipokines and cytokines on bone cells and the indirect effect of leptin on the sympathetic nervous system via hypothalamic nuclei. Obesity has variable effects on skeletal integrity and ultimately on future fracture risk. In individuals with increased subcutaneous fat, cortical bone mass may be enhanced due in part to loading on the outer surface of the skeleton.

On the other hand, increased visceral fat has been associated with decreased trabecular bone mass. This may be due to inflammatory cytokines that are released from visceral adipocytes, which differ from subcutaneous adipocytes both in origin and in function.

Thus, whether obesity is a risk factor for osteoporosis remains an important clinical question. Results of observational studies are inconsistent although there is emerging evidence that individuals with the metabolic syndrome, and hence increased visceral fat, have a greater risk of fracture despite normal bone density [113]. Similarly, in the MrOS cohort, most of the men in the study who had fractures were obese suggesting a potentially important gender-specific effect of adiposity on skeletal integrity [114]. Further studies are needed to define the precise relationship between obesity and osteoporosis. However, recent progress has been remarkable and there are likely to be therapeutic advances that could target both bone and fat to reduce the risk of osteoporosis and obesity.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Hormonal interactions between bone and fat
  5. Bone and metabolic disorders
  6. Role of marrow adipocytes in skeletal metabolism
  7. The function of marrow fat
  8. Implications for osteoporosis
  9. Significance of marrow adiposity
  10. Conclusions
  11. Conflict of interest statement
  12. References