Abstract
Reciprocal relationships between organs are essential to maintain whole body homeostasis. An exciting interplay between two apparently unrelated organs, the bone and the brain, has emerged recently. Indeed, it is now well established that the brain is a powerful regulator of skeletal homeostasis via a complex network of numerous players and pathways. In turn, bone via a bone-derived molecule, osteocalcin, appears as an important factor influencing the central nervous system by regulating brain development and several cognitive functions. In this paper we will discuss this complex and intimate relationship, as well as several pathologic conditions that may reinforce their potential interdependence.
Introduction
Whole-body homeostasis relies on the crosstalk between organs, which are essential to coordinate their activity and ensure proper regulation of their physiological functions. These dialogs are mediated by hormonal factors secreted into the bloodstream. Changes in environmental conditions due to biological stress or influence by other organs are sufficient to induce variations in circulating hormone levels, which travel to their target organs acting as far-reaching messengers. The brain has long been considered the main coordinator for the activities and hormonal secretion of other organs. However, multiple studies demonstrated the reciprocal dependence of the brain on the peripheral organs. Indeed, it is known that several peripheral hormones, such as insulin, leptin, thyroid hormones and sex steroid hormones can cross the blood-brain barrier (BBB) and reach the central nervous system (CNS), where they regulate brain development and modulate multiple aspects of cognitive functions [1], [2], [3], [4], [5], [6], [7], [8], [9]. Moreover, hormonal imbalances are also well known to elicit profound effects on the central regulation of food intake, energy expenditure and multiple physiological functions [10], [11], [12], [13]. Importantly, hormone levels are known to fluctuate with aging and elegant studies have recently demonstrated that blood derived from young mice can reverse the decline of hippocampal neurogenesis and memory-related behaviors [14], [15], [16]. Taken together these observations highlight the fundamental importance of endocrine cues and reciprocal interactions between organs for the maintenance of whole-body homeostasis and the function of the CNS.
The emergence of genetically engineered mouse models has revolutionized the entire field of physiology and endocrinology, allowing the identification of novel endocrine organs and hormones, as well as many unsuspected connections between organs. This is particularly true for the bone for which multiple genetic-based studies have shed light on the growing physiological importance of this organ in whole-body homeostasis [17], [18], [19]. Beyond the classical view of the skeleton describing it as a relatively static tissue, the bone secretes at least two molecules influencing whole-body homeostasis [18], [20], [21], [22], [23], [24]. First, fibroblast growth factor 23 (FGF23), a protein synthesized by osteoblasts and osteocytes and released into general circulation, regulates phosphocalcic metabolism in multiple tissues [21], [25], [26]. Second, it was shown that an osteoblast-derived molecule, osteocalcin (Ocn), does not act directly on bone but influences other physiological functions that in turn influences bone physiology. Indeed, Ocn promotes pancreatic β-cells proliferation, glucose homeostasis, enhances energy expenditure and prevents the appearance of glucose intolerance induced by high fat diet [18], [23], [27], [28]. Moreover, it was shown that Ocn may also influence the gonads by promoting testosterone biosynthesis in Leydig cells of the testis and thereby favors male fertility [18], [22], [29], [30], [31], [32]. The demonstration that bone affects such a variety of physiological functions suggests that the skeleton has important endocrine functions and leads us to ask how bone and bone derived factors influence other organs.
Since the early developments in anatomy and histology, the skeleton is known as a highly innervated tissue, suggesting a dialog occurring between the nervous system and the skeleton. Nevertheless, this hypothesis started to be explored in the early 2000s [33]. Using a combination of mouse and human genetic studies, it was shown that the brain, via the activation of the sympathetic nervous system (SNS), is a powerful negative regulator of bone growth [11], [34], [35], [36]. Since then, additional specific neuronal pathways and molecular players have been identified as important mediators of the complex central regulation of bone mass and will be discussed in this review. Importantly, it was recently shown that the bone may signal back to the CNS and influence brain development and cognitive functions. This influence relies on an osteoblast-derived molecule, Ocn and occurs at several stages throughout life. In adult mice, Ocn crosses the BBB and modulates several neurotransmitters content. As a result, it prevents anxiety and depression and favors spatial learning and memory. During embryogenesis, maternal Ocn crosses the placenta and influences brain development, as evidenced by the anatomical defects in the hippocampal region observed in the absence of Ocn, which lead to an impairment of memory functions in the offspring. Taken together, these observations strongly suggest the existence of an unexpected dialog between bone and brain, reinforcing the reciprocal dependence between these two organs.
In this review, we will discuss the crosstalk between bone and brain, from the first discovery of the central regulation of bone mass [33] until the recent discovery that the bone, via Ocn, is a determinant of brain development and behavioral functions [8]. Lastly, the bone-brain interaction is also supported by several clinical observations analyzing different brain pathologies, like schizophrenia and depression. These diseases will be discussed in the context of deciphering the important interplay between these two organs.
The regulation of bone mass by the CNS
Bone is an organ essential for locomotion and is defined primarily by its mechanical and scaffolding properties. Based on these characteristics, it is crucial for vertebrates to maintain a constant bone mass and high quality of bone throughout life. This is achieved in a biphasic process, called bone remodeling, which is control by two specialized bone cells: osteoblasts and osteoclasts, and allows the bone to constantly renew itself. The first phase of this process is the destruction of preexisting bone mediated by the osteoclasts followed by a second phase of de novo bone formation control by the osteoblasts. These two phases not only occur sequentially, but also occur in a balanced manner. Importantly, any disturbance in this balance, which can be linked to hormone disequilibrium or aging, results in bone pathologies, such as osteoporosis, one of the most common aged-associated diseases leading to increased vulnerability to fractures.
The skeleton has long been described as a highly innervated tissue [37] with sensory and autonomic neurons. However, the importance of the nervous system on bone physiology and turnover has begun to be deciphered over the past 15 years [18], [33], [34], [36] and there is now strong data showing that the brain is a powerful regulator of skeletal homeostasis via numerous players and pathways. Indeed, the CNS regulates bone mass either by the direct action of neurotransmitters that it produces or by acting as a mediator in processing peripheral hormonal signals, such as leptin, that originates from adipose tissue. In this section, we will present an overview of the central regulation of bone physiology.
The sympathetic nervous system
Bone remodeling occurs constantly and simultaneously in various parts of the body [17], [38], and requires a large amount of energy for the recruitment of osteoblasts and the deposition of extracellular matrix (ECM). Based on this notion, it was hypothesized that the bone remodeling process might be coordinated with the regulation of energy metabolism. Moreover, this hypothesis was supported by clinical observations showing a near total arrest of growth in childhood and low bone mass in adults presenting with anorexia nervosa [39], [40], [41], whereas adult obese patients display a higher bone mass that protects them from osteoporosis. These clinical observations suggested that bone mass shares regulatory mechanisms with energy metabolism.
Of all the hormones known to regulate energy metabolism, it appeared that leptin, an adipocyte-specific hormone [11], [10], [42], was the best candidate to test this hypothesis for various reasons. First, leptin regulates appetite, energy expenditure and fertility by signaling in the brain [33], [36], [34], [42], [43], [44], [45]. Second, leptin does not appear during evolution linked to any aspect of energy metabolism or reproduction, but is instead associated with bone (re)modeling. While exploring the potential role of leptin in bone mass regulation, it was shown that mice lacking leptin (ob/ob) or its receptor display a high bone mass phenotype due to a massive increase in bone formation [33], [35], [46]. Although in vitro studies have shown that leptin, under certain conditions, can affect osteoblast functions directly [47], several genetic pieces of evidence indicate that leptin acts on the CNS to inhibit the accrual of bone mass, which is consistent with other described functions of leptin. The most convincing argument is that neuron-specific deletion of the leptin receptor [46] recapitulates the bone phenotype of ob/ob mice whereas an osteoblast-specific deletion does not [18], [48]. Moreover, intra-cerebro-ventricular (ICV) infusions of leptin decreased bone mass and volume by decreasing osteoblast activity. Conversely, the same experiment performed in ob/ob mice restored their bone mass phenotype [33], [35], [36]. Even if it was shown in vitro that leptin can affect osteoblast functions directly, genetic evidence showed that this hormone inhibits bone mass accrual mainly by acting on the brain [18], [33], [47] indicating that leptin regulation of bone mass is mainly central.
Next, a set of experiments suggested that antiosteogenic action of leptin acts through the ventromedial hypothalamus (VMH). Indeed, chemical ablation of VMH neurons using gold thio-glucose (GTG) did not affect metabolic functions but resulted in a high bone mass phenotype that could not be corrected by ICV infusion of leptin [36]. Moreover, both ob/ob mice as well as GTG-treated mice had low levels of catecholamines which is the major neurotransmitter of the SNS, suggesting that the sympathetic tone may mediate the leptin regulation of bone mass. Testing this possibility, it was shown that knock-out mice for the beta-2 adrenergic receptor (Adrβ2R-/- mice), one of the receptors mediating catecholamine norepinephrine action in the cells, produced a phenocopy of bone features seen in ob/ob mice. In contrast, bone mass remained unchanged in Adrβ2R–/– mice when leptin was infused by ICV. Taken together, these results indicate that the SNS, acting through Adrβ2R, is necessary and sufficient to mediate central leptin action on bone mass accrual.
Based on the high bone mass phenotype obtains after chemical ablation of the VHM, it was assumed that the hypothalamus was the only site of action for leptin in the brain [42]. However, it was demonstrated that selective inactivation of the leptin receptor in VMH-neurons did not recapitulate the phenotype observed in ob/ob mice [49] suggesting that leptin might also signal elsewhere in the brain. Accordingly, Yadav et al. [50] detected a major increase of serotonin in the brainstem of mice lacking leptin receptor, while leptin brain infusions in WT mice decreased the serotonin content in the brain. Clinical insights also support the notion that serotonergic circuits might be implicated in the central regulation of bone mass. In fact, it is widely accepted that patients under serotonin reuptake inhibitors (SSRIs), widely used antidepressants that increase the level of serotonin in the brain by limiting its reabsorption into the presynaptic cell, develop low bone mass phenotype. It is known that serotonin is only synthetized in the raphe nuclei of the brainstem where the rate-limiting enzyme Tph2 (tryptophan hydroxylase 2) catalyzes the conversion of tryptophan to 5-hydroxytryptophan (5-HT) [50]. Based on the possibility that leptin regulates, at least in part, bone mass via an influence that it may exert on the serotonergic system, it was shown that Tph2–/– mice exhibit low bone mass phenotype. Moreover, axonal-tracing analyses revealed that serotonergic neurons of the brainstem are able to project toward the VMH region of the hypothalamus, demonstrating an anatomical connection between these two systems. Lastly, the intracellular cascade activated by the serotonergic system in the VMH involves the binding of serotonin to its receptor Htr2c in VMH neurons and triggers a CaMK/CREB-dependent signaling cascade involving CaMKKβ and CaMKIV to decrease the sympathetic tone and consequently to increase bone mass accrual [51].
Recently, it was also shown that adipocytes secrete another hormone, adiponectin, that may also influence the central regulation of bone mass accrual. This hormone exhibits opposite effects of leptin by increasing the sympathetic tone and, consequently, decreasing bone mass accrual [52].
The parasympathetic nervous system
The autonomic nervous system is composed of two branches, the SNS and the parasympathetic nervous system (PNS), which have opposite functions. While the SNS primary process is to stimulate the body’s “fight or flight” response, the PNS is responsible for stimulation of “feed and breed” activities when the body is at rest. In most organs and in order to maintain the whole-body homeostasis, the activity of one branch is counterbalanced by the other. Indeed, the demonstration that the SNS tightly regulates bone mass raised the question of whether the other arm of the autonomic nervous system, the PNS, may also affect the central regulation of bone mass (Figure 1).
![Figure 1: The central regulation of the bone physiology relies.The central regulation of the bone physiology relies on multiple nervous system and neuronal players.The autonomous nervous system [composed by the sympathetic (SNS) and parasympathetic nervous system (PNS)], the sensory nervous system, some hypothalamo-pituitary-derived hormones [thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), oxytocin (OT), prolactin (PRL) and arginine-vasopressin (AVP)] and other brain-derived molecules, such as the cocaine amphetamine regulated transcript (CART), the neuromedin U (NMU) and the neuropeptide Y (NPY).](/document/doi/10.1515/hmbci-2016-0030/asset/graphic/j_hmbci-2016-0030_fig_001.jpg)
The central regulation of the bone physiology relies.
The central regulation of the bone physiology relies on multiple nervous system and neuronal players.
The autonomous nervous system [composed by the sympathetic (SNS) and parasympathetic nervous system (PNS)], the sensory nervous system, some hypothalamo-pituitary-derived hormones [thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), oxytocin (OT), prolactin (PRL) and arginine-vasopressin (AVP)] and other brain-derived molecules, such as the cocaine amphetamine regulated transcript (CART), the neuromedin U (NMU) and the neuropeptide Y (NPY).
The PNS functions are mediated by acetylcholine (ACh) [53], which is released by the preganglionic neurons in the CNS and stimulates the postganglionic neurons in the periphery. ACh activates the target organs by binding to the metabotropic G-protein coupled receptor, muscarinic ACh receptors, of which five have been described so far (M1R to M5R) [54]. In testing the potential role of the PNS in the regulation of bone homeostasis, it was first demonstrated that the skeleton is innervated by cholinergic neurons [55], [56]. In addition, a cell-specific deletion of M3R in neurons induced a low bone mass phenotype, indicating that the PNS can favor bone mass accrual through a central relay. This is further supported by the fact that cholinergic agonists enhance bone resorption that follows osteoclast apoptosis and osteoblast proliferation [55], [56]. Lastly, the analysis of the Adrβ2+/–;M3R +/– compound mutant mice [54], in which one allele of the M3R and one allele of the adrenergic receptor Adrβ2 have been removed, present a normal bone mass suggesting that the PNS may promote bone mass formation by inhibiting the SNS (Figure 1). By showing that both branches of the autonomic nervous system affect bone remodeling, it further underscores the importance of neuronal regulation of bone by the brain.
Other neuronal systems influencing bone mass accrual
There is now evidence showing that the SNS and PNS are not the only neuronal systems influencing the regulation of bone mass. Recent studies have demonstrated that other neuronal system and neurotransmitters are also implicated in this complex regulation.
The sensory nervous system is one of them and might positively regulate bone mass by counterbalancing the powerful effect of the SNS (Figure 1). One example of this regulation is the role of semaphorin 3A (Sema3A), a powerful osteoprotector secreted by osteoblasts [57], [58]. Sema3A belongs to a family of axonal guidance cues and serve as chemo-repellents during the development of the nervous system [59]. Interestingly, Sema3A–/– mice exhibit a low bone mass phenotype resulting from increased osteoclastic activity, which is only observed after Sema3A inactivation in neurons but not in osteoblasts [58], [60]. Anatomical analysis of Sema3A–/– mice showed a specific defect in sensory innervation while sympathetic innervations remained unchanged [60].
The hypothalamic-pituitary axis is an important component of our CNS. The hypothalamus delivers precise signals to the pituitary gland, which then releases hormones that influence most the endocrine systems. It is already known that this axis influences indirectly bone physiology via the hormones that it secretes in the bloodstream. However, recent studies have also described that some hormones secreted by the pituitary gland bypass their classical targets in order to act directly on the skeleton and to regulate bone remodeling. The first demonstration of this effect was the identification of thyroid stimulating hormone (TSH) as a direct regulator of bone mass (Figure 1). TSH is an anterior pituitary hormone known as the major regulator of T3 and T4 secretion from the thyroid gland. However, TSH has been also identified as an inhibitor of bone formation and resorption via its direct action on bone cells [61]. In osteoblasts, TSH down-regulates important transcription factors important for osteoblast differentiation and proliferation, such as Runx2, Osterix and Lrp5. In osteoclast, TSH modulates the osteoclastic activity by inhibiting the phosphorylation of JNK and IκBα, which decreases NFκB activity, preventing expression of AP1 genes and TNFα [61], [62], [63]. In addition to TSH, other hypothalamo-pituitary hormones have been also recently identified as direct regulators of bone mass. First, an elegant study performed in humans showed that the onset of osteoporosis in women at perimenopause is associated with increasing levels of the follicle stimulating hormone (FSH) [64]. These data depict a mechanism whereby FSH antagonizes sex steroid action in bone targeting osteoclasts and up-regulating bone mass accrual [65] (Figure 1). Second, prolactin (PRL), a small peptide hormone secreted by the anterior pituitary gland [66], might also directly enhance osteoclast activity, and consequently bone turnover [67], [68], [69] (Figure 1). Third, the primitive mammalian neurohypophyseal hormone, oxytocin (OT) [66], stimulates osteoblast differentiation by up-regulating BMP-2 expression and osteoclast formation through the activation of NF-κB and MAP kinase signaling [66] (Figure 1). Lastly, using pharmacological, genetic and in vitro assays, it was shown that arginine-vasopressin (AVP), a hormone secreted by the posterior pituitary gland, decreases osteoblast proliferation while increasing osteoclastic activity through its receptor Avpr1 and Avpr2 [70] (Figure 1).
Additional peptides and neurotransmitters involved in the central regulation of bone mass
Several neuromodulators have been identified as potential regulators of the central control of bone mass and have been added to the large network of players involved in this complex regulation of the bone turnover (Figure 1). These neurotransmitters and peptides act mainly through the hypothalamo-bone pathway, dependently or independently of leptin functions. First, neuropeptide Y (NPY), a neuropeptide produced in various part of the brain, has recently emerged as a regulator of bone turnover [71]. NPY acts on bone remodeling by decreasing osteoblast activity, through the activation of its receptor Y2 present in the hypothalamic neurons of the brain. Second, recent studies have also characterized the role of neuromedin U (NMU), as a negative factor in regulating bone mass accrual, via its binding to NMU receptor 2 (NMUR2) in the hypothalamus [72]. Third, a neuropeptide produced in the ventral tegmental area of the brain, the cocaine amphetamine regulated transcript (CART), acts as a mediator of leptin in the CNS [34], [73], [74]. As a result, the absence of CART enhances bone resorption similarly to what is reported in leptin-deficient mice [34]. Lastly, a selective inactivation of the brain derived neurotrophic factor (BDNF) in the brain results in a high bone mass phenotype with no change regarding the sympathetic tone [75].
The growing importance of the CNS and the large network of players involved in the regulation of the bone turnover is a demonstration of the crucial importance of the brain in the regulation of bone physiology and functions, but has also paved the way for the genuine and yet crucial question: can bone regulate or influence the brain?
Bone is a novel endocrine organ that influences brain development and functions
Bone as an endocrine organ
Over the last 15 years, the physiological importance of bone has considerably evolved towards a more complex picture of this organ. It is now well established that the skeleton is not only a recipient for hormonal input, but it also secretes molecules, at least two, in the bloodstream, influencing the physiological functions of various tissues.
The first described bone-secreted molecule is FGF23, a protein synthesized by osteoblasts and osteocytes. FGF23 is known as an important regulator of the phosphocalcic metabolism, decreasing serum levels of inorganic phosphate by inhibiting renal and gut phosphate reabsorption [20], [25], [26], [76]. In addition, FGF23 suppresses the production of 1, 25(OH)2 vitamin D3 by inhibiting 1α hydroxylase. To regulate phosphate resorption FGF23 binds to a protein complex composed of FGFR1 and the co-receptor klotho. It is still an open question whether FGF23 has additional physiological functions (Figure 2).
Bone is an endocrine organ.
The demonstration that the skeleton secretes at least two molecules in the bloodstream that will influence functions of other organs has considerably increased the physiological importance of the bone. Through the secretion of FGF23, bone influences the phosphocalcic metabolism by inhibiting renal and gut phosphate reabsorption. Second, via the secretion of osteocalcin (Ocn), bone promotes pancreatic β-cells proliferation, glucose homeostasis, enhances energy expenditure and prevents the appearance of glucose intolerance induced by high fat diet. Moreover, it also enhances testosterone biosynthesis in Leydig cells of the testis and thereby favors male fertility. Lastly, it was shown recently that Ocn may also influence brain development and functions.
The second molecule secreted by the bone is Ocn, a small peptide (46 amino acid-long in mice) synthetized by osteoblasts, which can be γ-carboxylated on 3 glutamic acid residues [18], [23], [77], [78]. Ocn is the most abundant non-collagenous protein of the bone ECM and can also be found in the general circulation. Importantly, its mode of activation is a two-step process that relies on the interplay between osteoclasts and osteoblasts. Osteoblasts produce and secrete an inactive carboxylated form of Ocn that is mainly stored in the bone matrix. The activity of the osteoclasts creates a resorption lacuna with a low pH (4.5). This low pH is necessary and sufficient to transform the inactive form of Ocn into its active form by decarboxylation [27], [79]. This feature of Ocn and the fact that it is so abundant in mineralized ECM suggested that it is involved in bone ECM mineralization [80]. However, loss- and gain-of-function mutations in Ocn have unambiguously established that this is not the case [18], [28]. Rather, Ocn influences, via a feedback loop, important regulators of bone physiology. It was shown that Ocn favors proliferation of pancreatic β-cells, secretion of insulin and insulin sensitivity in both muscle and white adipose tissue. As a result, Ocn promotes glucose homeostasis, enhances energy expenditure and prevents the appearance of glucose intolerance induced by high fat diet (Figure 2). Moreover, Ocn favors male reproductive functions in mice by promoting testosterone biosynthesis by the testis, following its binding to a receptor expressed in Leydig cells, Gprc6a, that belongs to the G-protein coupled receptor family [24], [29], [30], [31], [81] (Figure 2). It was also shown that Gprc6a is expressed in pancreatic β-cells and that it is also the receptor mediating Ocn influences on the energy metabolism [32]. Lastly, taking advantage of this unique fertility phenotype observed in Ocn–/– and in Gprc6a–/– mice that recapitulates the well-defined syndrome in human called “primary testicular failure”, the biological relevance of the endocrine role of Ocn was investigated in humans. Indeed, genomic analysis of a cohort of patients presenting this syndrome identified two individuals harboring the same point mutation, acting as a dominant negative mutation of GPRC6A. Furthermore, these two patients presented similar metabolic abnormalities to the ones observed in Ocn–/– and in Gprc6a–/– mice.
As bone affects multiple physiological functions following a feedback loop, it was natural to test whether the skeleton could influence the brain directly or indirectly. Interestingly, the observation that Ocn-deficient mice are significantly less active than WT littermates led us to hypothesize that Ocn might influence certain brain functions. This is supported by several skeletal dysplasiae affecting bone formation and are associated with cognitive impairment. An example is the cleidocranial dysplasia (CCD), a disease caused by haplo-insufficiency of RUNX2, which is one of the two major transcription factors regulating expression of Ocn and that will be discussed further [82], [83], [84].
Osteocalcin and its functions in adult brain
The passivity of Ocn–/– mice was further explored by a battery of behavioral tests that revealed that these mice exhibit an increase in anxiety and depression-like behaviors, coupled with a decrease in memory function [8] (Figure 3). These behavioral impairments may be explained by the fact that the content of three monoamine neurotransmitters: norepinephrine, dopamine and serotonin are decreased in the absence of Ocn (Figure 3). Conversely the GABAergic tone is widely increased in the brain. As discussed earlier, the decrease in norepinephrine content observed in the brains of Ocn–/– mice may help to explain the high bone phenotype originally noted in this model [85]. It is important to note that the Gprc6a–/– mice are indistinguishable from WT littermates. This makes it unlikely that this receptor transduces Ocn signals in the brain. This last notion is also important because it implies that the passivity of the Ocn–/– mice is not a mere consequence of metabolic or reproductive abnormalities, since these are equally severe in Ocn–/– and Gprc6a–/– mice [24], [30], [86], [87].
Embryonic and postnatal influence of Ocn on brain.
Mother-derived osteocalcin crosses the placental barrier from E14.5 until birth and influences brain development by preventing neuronal apoptosis. This action is essential to maintain spatial learning and memory-like behavior functions of the offspring. Postnatally, bone-derived Ocn crosses the BBB and influences the production of several neurotransmitters: serotonin, dopamine, norepinephrine and GABA, prevents anxiety- and depression-like behavior, favors memory-related functions, and enhances adult hippocampal neurogenesis (AHN).
Together, these observations were the first demonstration that Ocn could influence brain function. However, it did not determine whether Ocn’s regulation of brain behavioral functions derived from a direct or indirect action of this molecule on the CNS. Addressing this question, it was next shown that Ocn is not expressed in any part of the brain, but is capable of crossing the BBB and binds to several regions in the brain, such as the hippocampus, the ventral tegmental area and the substantia nigra (two dopaminergic nuclei located in the midbrain), as well as the brainstem (containing all of the serotonergic neurons of the brain) [8] (Figure 3). Lastly, electrophysiological analyses and calcium flux measurements demonstrated a direct action of Ocn in neurons suggesting that this molecule may exert a neuro-active function.
As mentioned, postnatal inactivation of Ocn [8] produced a significant increase in anxiety- and depression-like behaviors, demonstrating a postnatal effect of Ocn on these functions. In contrast, spatial learning and memory were only modestly affected in these mice. In this line, ICV infusion of Ocn in Ocn–/– adult mice is able to fully rescue anxiety- and depression-like phenotypes, while the spatial learning and memory defects are only partially restored. Taken together, these observations show that Ocn influences memory-like behavior both during adulthood and embryogenesis, while the anxiety- and depression-like phenotypes were specific in a postnatal role of this hormone. Lastly, it was also suggested a role of Ocn in adult hippocampal neurogenesis, particularly in the dentate gyrus area [8].
Maternal osteocalcin influence brain development
During embryogenesis, endogenous Ocn expression was not detected in the skeleton of the mouse until embryonic day 16.5 (E16.5), but the protein was already detectable in the blood of E14.5 embryos. This suggests an exogenous source of this molecule coming from either the placenta or from the maternal Ocn reaching the fetal blood stream. Further experiments demonstrated that Ocn is not expressed in the placenta, but it is able to cross it [8], which indicates that the embryonic Ocn is from maternal origin. In the absence of maternal and endogenous Ocn, embryos show an enlargement of the lateral ventricles of the brain and an increase in the number of apoptotic cells in the hippocampus. However, daily injections of Ocn to Ocn–/– mothers during pregnancy corrected this anatomical phenotype but also partially rescued the deficit in learning and memory of the offspring. This observation indicates that the effect of Ocn on memory is not only postnatal but also developmental and most predominantly from a maternal origin (Figure 3).
Neuropsychiatric diseases and bone physiopathology
Retrospectively, several clinical observations and correlative studies have already emphasized a potential physiological link and/or common signaling mechanisms between bone and brain. Indeed, some specific bone diseases derived from genetic mutations in genes encoding specific osteoblastic and/or osteoclastic molecules are also associated with neurological disorders. Conversely, many neurological diseases are accompanied by impaired bone health and increased risk of fracture. As an example, Alzheimer’s disease (AD) and osteoporosis are two of the most common chronic age-associated degenerative disorders. Interestingly, recent studies have linked disruption of bone homeostasis during aging with increased risk of mild cognitive impairment in AD. Moreover, it was also demonstrated that patients with AD develop adverse characteristic for osteoporosis and increased bone turnover activity compare to healthy people of the same age [88], [89], [90], [91], [92], [93], [94], [95].
In this section, we will give a brief overview of the clinical studies describing either bone diseases with associated cognitive impairment or neurological disturbances associated with bone abnormalities, adding supporting evidence to the close interaction and potential reciprocal dialog between bone and brain. Nevertheless, multiple factors contribute to the development of osteoporosis including age, gender, height, weight, family history, smoking status and vitamin D levels [95]. It is important to mention that this section is only based on correlative studies and that the potential direct or indirect role of the bone in neuropsychological disorders needs to be further directly explored by clinical and animal studies.
Age-related cognitive disorders and osteoporosis
Age-related memory loss
In healthy individuals, cognitive impairment develops around midlife, and one of the most commonly affected cognitive function is memory. With the increase in life expectancy, the number of individuals affected with age-related memory loss is bound to increase. Therefore, one of the major challenges is to extend the resilience of our body functions and health-span during aging. A deeper understanding of how a healthy brain ages and defining the mechanisms of age-related cognition deficits are a priority in order to treat age-related cognition deficits common in the elderly population.
The fact that the spectrum of these irreversible disorders is wide and that no effective therapy exists at the moment urges a better understanding and therapeutic management of these disorders [96]. Particular to our interest, the age-related cognitive decline and tendency to dementia has been negatively correlated with bone mass density. In two large population studies, it was found that people in the lowest quartile of bone density had a two-fold increased risk of dementia [89], [97], adding support to the notion that disruption of bone may be associated to cognitive and aging processes.
Alzheimer’s diseases (AD)
Osteoporosis and AD are the two most common aged-associated diseases [91], [98] and epidemiological findings reveal that both diseases have very high comorbidity. However, the mechanisms underlying their association are still unknown.
AD accounts for 60%–70% of all cases of dementia and is characterized by progressive deterioration of cognitive functions and stress [99], [100]. Prevalence of AD rises exponentially with age, increasing drastically after 65 years of age [96], [101]. The causes of AD are still under current investigation, but the disease is characterized by biochemical alterations resulting in the accumulation of amyloid-β (Aβ) protein in the form of senile plaques and intracellular neurofibrillary tangles, associated with hyperphosphorylated tau protein and neuronal cell depletion [102]. Interestingly, these markers of neurodegeneration have been detected in tissues outside of the CNS, like osteoporotic bone tissue. Indeed, using transgenic mice that express an AD-associated mutant form of amyloid precursor protein (APP), Xia and collaborators explored the effects of mutant APP on bone [103]. From a young age, these mice displayed defects in bone formation when compared to wild-type controls. However, whether abnormal Aβ peptide (Aβ) deposition also occurs in osteoporosis and the relationship between Aβ and human osteoporosis remains an open question [102].
Recently, correlative clinical studies demonstrated that AD is frequently associated with fractures and reductions of the bone mineral density (BMD), even at early stages of the disease when patients are still active [93], [94]. This observation has been confirmed by numerous reports suggesting that low BMD is linked with increased risk of mild cognitive impairment to AD [93], [94], [104]. Lastly, it has been found that patients with AD have increased bone turnover and risk of osteoporotic hip fractures [88], [89]. However, the mechanisms underlying their association are still poorly understood.
Hormonal factors are increasingly recognized to play an important role in AD pathogenesis of AD and dementia [105]. Based on recent evidence showing that Ocn regulates hippocampal-dependent memory function, that aging is associated with a decrease in circulating levels of Ocn and that AD and osteoporosis may share conserved pathogenic mechanisms, it incites to investigate further the relation between Ocn and AD.
Bone diseases associated with cognitive impairments
Cleidocranial dysplasia
The discovery of major determinants of osteoblastic and osteoclastic differentiation was made through clinical studies. The osteoblast-specific transcription factor of osteoblast differentiation, RUNX2, was identified through genetics studies in patients with CCD. CCD is mainly caused by haploinsufficience of RUNX2 [82], [83], [84], leading to clavicular hypoplasia, delayed cranial sutures, wide spectrum of dental abnormalities and small body shape. Interestingly, some patients harboring CCD also develop cognitive disorders due to still unknown mechanisms [29], [106]. This observation might be correlated with the influence of Ocn on the brain development and cognitive functions. In fact, RUNX2 is a major osteoblastic transcription factors, which in turn regulates expression of Ocn [82], [83], [84]. Taken together, these data suggest that the skeleton, via the Ocn functions, might be a potent determinant for the neuropsychological symptoms observed in these patients and incite to investigate further this relationship.
Coffin-Lowry syndrome
Coffin-Lowry syndrome (CLS) is a rare genetic disorder characterized by craniofacial and skeletal abnormalities in many parts of the body. CLS patients exhibit delayed growth with short hands and characteristic facial dysmorphisms. The signs and symptoms are usually more severe in males than in females, although a range from very mild to severe is observed in affected women. Importantly, CLS patients have also profound mental retardation with intellectual disability and delayed development [107] which become more pronounced with age.
This disorder is caused by loss-of-function mutations in the X-linked gene RSK2, which encodes a growth- factor-regulated protein kinase that phosphorylates ATF4 [108], [109], [110]. ATF4, a major osteoblast differentiation factor, is required in the brain for the induction of long-term potentiation, a form of synaptic plasticity that is crucial for memory formation [111], [112]. In addition, ATF4 phosphorylation is required in bone for osteoblast differentiation, and consequently to increase Ocn production [109], [110]. Consequently, based on the recent disclosure of bone regulation on memory and the mental retardation observed in CLS, it is reasonable to hypothesize a link between the mental deficits observed in CLS and the disruption of osteoblastic differentiation due to a decline in ATF4 activity.
Complex regional pain syndrome
Complex regional pain syndrome (CRPS) is a multifactorial disorder of complex pathogenesis accompanied by a rapid demineralization of bone. This syndrome affects one or several joints and the surrounding bones, and results in continuous pain, joint stiffness and vasomotor disturbances. Importantly, the CRPS is also often characterized by the emergence of psychiatric diseases such as depression, anxiety and personality disorders [113]. It may be of significant value to address the osteo-articular defects with regard to the psychological consequences of this disease. In addition, the growing importance of the regulation of bone physiology via the nervous system may lead to understand some features of this syndrome and contribute to the development of the unprecedented mechanism-based therapies [113].
Osteopetrosis
The osteopetrosis are caused by reduced activity of osteoclasts which results in defective remodeling of bone and increases bone density [114]. There are different types of osteopetrosis. One of them, the Nasu-Hakola syndrome, is a genetically heterogeneous disease characterized by a unique combination of systemic bone cysts and dementia with psychotic symptoms similar to schizophrenia. This syndrome is the result of a loss of function mutation in the DAP12 gene located in chromosome 19 [115]. MRI and neuropathological studies of Nasu-Hakola patients have demonstrated the development of calcifications in the basal ganglia and also that frontal lobe syndrome and that dementia begins to develop by age 30. Interestingly they found that some patients do not show any bone symptoms and signs before the onset of neurologic manifestations [83]. Moreover, it was also shown that mutant mice presented synaptic degeneration and electrophysiological analysis have shown impairments in GABAergic transmission, a feature that is generally observed in human neuropsychiatric diseases [116].
Mutations in other genes have been identified as being involved both in the development of osteopetrosis and neurological impairments, such as Ostm1. Interestingly, Ostm1 is both highly expressed in the mouse brain and osteoclasts. Ostm1–/– mouse brain showed an increase of astrocyte cell population and microglia activation associated with marked massive neuronal loss in the brain. Intracellular characterization of neurons revealed abnormal autophagy activity and a significant down-regulation of the mammalian target of rapamycin signaling. Complete functional analysis demonstrated the development of severe and rapid neurodegeneration [117].
Neuropsychological disorders associated with bone physiological defects
Major depressive disorder
Major depressive disorder (MDD) is known as the most prevalent diseases worldwide [118]. This disease remains a major challenge of public health because of its high frequency and inconsistent response to available treatments [118]. The MDD is defined by a disproportionate and persistent sadness in the absence of manic episodes, which are in contrast characterized by hyperactivity, euphoria and increased seeking of pleasure [119].
It appeared recently that the MDD is intimately associated to bone metabolism defects. Clinical studies have correlated features of bone metabolism in women with MDD indicating that depressed women had lower bone mass and lower levels of Ocn compared to healthy subjects [120], [121]. Moreover, it is known that the antidepressant drugs SSRIs decrease bone mass and increase the risk of fractures, which is consistent with the role of brain-derived serotonin on bone physiology [118], [122], [123], [124], [125]. Interestingly, it was shown that skeletal health in patients with past, but not current history of MDD was comparable to the one of healthy participants, suggesting that bone mass has been normalized after SSRI treatment. In addition, the main theories that prevail to understand the basis of this disorder is that MDD could be due to a deficit in brain monoamines serotonin and norepinephrine [119], two neurotransmitters affected in absence of Ocn. Consistent with these results, additional studies demonstrated a prevalent low BMD even at early stages of MDD excluding potential drug-induced bone loss. Combined with evidence from mice, these data provide an appealing ground for considering the skeleton as potent determinant of depression in human patients.
Schizophrenia
Schizophrenia is one of the most prevalent chronic and severe psychiatric disorders affecting approximately 1% of the general population. The symptomatology generally appears sequentially, the first symptoms being cognitive and social impairment, followed by anxiety and depression, and eventually prodromal symptoms leading to psychosis with paranoia and hallucinations [126]. It is suggested that the pathogenic mechanisms of the disorder are linked to the disruption of the dopaminergic system and derived from neurodevelopmental defects, including enlargement of the ventricles and gray and white matter disruptions [126], [127], [128]. Schizophrenia has been associated with a greater prevalence of health problems, including obesity, diabetes, metabolic syndrome and osteoporosis. However, the real cause of the schizophrenia is still under investigation. Interestingly, various reports have suggested a potential association between schizophrenia and low bone mass [129]. Surprisingly and in contrast to what was observed in depressive patients, a higher concentration of Ocn in the serum was reported for some schizophrenic patients [129]. Given similar behaviors and abnormalities observed in Ocn–/– and schizophrenic patients, this can be yet unexplored path to link bone and schizophrenia.
Conclusion
As the demonstration that skeletal homeostasis is strongly regulated by the SNS, several additional neuronal players involved in this regulation has emerged. These observations highlight the complexity of the control of bone mass but also indicate that the CNS is truly a key regulator of bone physiology. More recently, the fact hat bone, via Ocn, signals back to the CNS supports the notion that the skeleton is not only a static tissue composed by an assembly of inert calcified tubes but a functionally complex organ with important physiological functions. Moreover, it also opened the door to the exploration of an intimate relationship between bone and brain, which is emphasized and nourished by several clinical observations and correlative studies suggesting a functional dialog between these two organs, or at least, that they share some common regulatory mechanism.
Although the mechanisms underlying this association remain still poorly understood and that this association in human relies only on correlative clinical studies, the set of data discussed here suggests an exciting crosstalk between two apparently unrelated organs and reinforces the idea that a mutual dependence between organs is essential for the maintenance of our whole body homeostasis. Of course, further clinical/experimental studies are now needed to firmly demonstrate this close interaction and decipher the physiological importance of this dialog.
Acknowledgments
This work was supported by the Fondation pour la Recherche Medicale (FRM) grants FRM: AJE20130928594, the Human Frontier Scientific Program (HFSP) – CDA and the ATIP-AVENIR Program – INSERM. Lastly, we thank Dr. Nicolas Kuperwasser for critical reading of the manuscript.
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