骨骼生长发育中生长激素释放肽的重要作用

文题释义：生长激素释放肽(Ghrelin)：也被称为饥饿素及内源性脑肠肽，20世纪80年代人们通过从大鼠胃组织中分离提取出一种多肽类激素，发现其具有促进生长激素分泌而被命名为生长激素释放肽。 骨代谢：骨的功能是为肌肉收缩提供附着处及保护内脏等重要的生命器官。一般认为骨在细胞水平上是不活跃的，事实上骨的细胞在不停地进行着细胞代谢，不仅骨的细胞之间会相互作用，还存在骨髓中的红细胞生成细胞、基质细胞相互作用，以进行骨的改建和重建。 背景：生长激素释放肽具有促进生长激素分泌、调节机体能量代谢平衡及一些尚在探索的药理学特性，这些都与机体代谢状态密切相关。 目的：就生长激素释放肽对于骨骼细胞功能的调节及其在骨代谢和能量代谢中的整合作用做一综述，以期阐明生长激素释放肽在骨骼发育过程中发挥的重要作用。 方法：检索 PubMed数据库1993年1月至2017年1月相关文献，检索词为“ghrelin，Bone metabolism，leptin，osteoblast，osteoclast，castric resection，cartilage cells”。排除重复研究及与综述内容关系不密切的文献，对最终纳入的74篇文献进行分析。 结果与结论：机体骨骼系统的重塑是一个高度耗能的过程，与之相应的是，骨骼的生长发育涉及到外周和中枢的能量代谢，包括交感神经系统和瘦素等激素的作用。国外研究表明，生长激素释放肽能够调节成骨细胞的分化和功能，诱导骨髓干细胞的增殖及分化，通过不同的方式调节生长激素-胰岛素轴的状态，并能够通过与瘦素相作用来调配骨骼代谢与机体能量代谢从而影响骨骼的生长状态。 ORCID: 0000-0003-1053-8093(叶楠) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

The neurobiology of human obesity

Earlier ideas that sympathetic nervous system activity is low in human obesity, contributing to weight gain through absence of sympathetically mediated thermogenesis, can now be discounted. The application of sympathetic nerve recording techniques and isotope dilution methodology quantifying neurotransmitter release from sympathetic nerves has established that the sympathetic outflows to the kidneys and skeletal muscle vasculature are activated in obese humans. The cause remains unclear. The adipocyte hormone, leptin, stimulates the sympathetic nervous system in rodents, but whether this applies in humans is uncertain. Cross-sectional studies suggest a quantitative link exists between regional sympathetic nervous tone (most notably in the kidneys) and rates of leptin release, but definitive studies documenting that leptin administration activates the human sympathetic nervous system have not been done. What might be the clinical implications of these new findings? The demonstration that the suppressed sympathetic tone characterizing many experimental models of obesity does not exist in human obesity weakens the case for the use of beta3-adrenergic agonists as thermogenic agents to facilitate weight loss. Although the neurogenic character of obesity-related hypertension is now established, whether antiadrenergic antihypertensive drugs are the preferred agents for blood pressure reduction has not been adequately tested. Multiple site central venous sampling, disclosing release of leptin into the internal jugular veins, led to the demonstration that the leptin gene is also expressed in the brain, in addition to adipocytes. Brain resistance to leptin has been inferred in human obesity, given that overweight is accompanied by high plasma leptin levels. The fact that the genes for leptin and its receptors are normally expressed in the brain in human obesity, and that release of leptin from the brain is actually increased, argues against this. Brain leptin release has the potential to override the peripheral, adipocyte leptin system.     

The roles of the sympathetic nervous system in osteoporotic diseases: A review of experimental and clinical studies

With the rapid aging of the world population, the issue of skeletal health is becoming more prominent and urgent. The bone remodeling mechanism has sparked great interest among bone research societies. At the same time, increasing clinical and experimental evidence has driven attention towards the pivotal role of the sympathetic nervous system (SNS) in bone remodeling. Bone remodeling is thought to be partially controlled by the hypothalamus, a process which is mediated by the adrenergic nerves and neurotransmitters. Currently, new knowledge about the role of the SNS in the development and pathophysiology of osteoporosis is being generated. The aim of this review is to summarize the evidence that proves the involvement of the SNS in bone metabolism and to outline some common osteoporotic diseases that occur under different circumstances. The adrenergic signaling pathway and its neurotransmitters are involved to various degrees of importance in the development of osteoporosis in postmenopause, as well as in spinal cord injury, depression, unloading and the complex regional pain syndrome. In addition, clinical and pharmacological studies have helped to increase the comprehension of the adrenergic signaling pathway. We try to individually examine the contributions of the SNS in osteoporotic diseases from a different perspective. It is our hope that a further understanding of the adrenergic signaling by the SNS will pave the way for conceptualizing optimal treatment regimens for osteoporosis in the near future.     

Potential mechanisms linking psychological stress to bone health

Chronic psychological stress affects many body systems, including the skeleton, through various mechanisms. This review aims to provide an overview of the factors mediating the relationship between psychological stress and bone health. These factors can be divided into physiological and behavioural changes induced by psychological stress. The physiological factors involve endocrinological changes, such as increased glucocorticoids, prolactin, leptin and parathyroid hormone levels and reduced gonadal hormones. Low-grade inflammation and hyperactivation of the sympathetic nervous system during psychological stress are also physiological changes detrimental to bone health. The behavioural changes during mental stress, such as altered dietary pattern, cigarette smoking, alcoholism and physical inactivity, also threaten the skeletal system. Psychological stress may be partly responsible for epigenetic regulation of skeletal development. It may also mediate the relationship between socioeconomic status and bone health. However, more direct evidence is required to prove these hypotheses. In conclusion, chronic psychological stress should be recognised as a risk factor of osteoporosis and stress-coping methods should be incorporated as part of the comprehensive osteoporosis-preventing strategy.     

Metabolic modulation of sympathetic vasoconstriction in exercising skeletal muscle

The tight coupling of oxygen supply and utilization in exercising skeletal muscle is the result of complex interactions between local mechanisms that control muscle blood flow and substrate utilization and systemic mechanisms that control cardiac output and arterial pressure. The role of the sympathetic nervous system in the integration of these responses, specifically the interaction between sympathetic activation and local vasodilator mechanisms in exercising muscle, has been an active area of research for many years yet remains incompletely understood. The functional consequence of sympathetic activation in exercising skeletal muscle has been the subject of considerable debate. Previous studies in animals and humans have suggested that sympathetic vasoconstricton in active muscle is (a) well maintained and serves to limit active hyperaemia, thereby preventing muscle blood flow from outstripping cardiac output in order to preserve blood pressure and vital organ perfusion or (b) greatly attenuated in order to optimize muscle perfusion, a concept that has been termed 'functional sympatholysis'. Studies performed over the past 70 years have provided conflicting evidence regarding the relative importance of sympathetic vasoconstriction vs. functional sympatholysis in exercising skeletal muscle. The focus of this review is mainly on recent studies in anaesthetized animal preparations and in conscious humans that have provided evidence for the metabolic modulation of sympathetic vasoconstriction in contracting skeletal muscle and have identified a number of key underlying mechanisms that extend the initial concept of sympatholysis.     

An intact central nervous system is not necessary for insulin-mediated increases in leg blood flow in humans

Insulin mediates an increase in blood flow in the skeletal muscle. This may be brought about through recruitment of sympathetic vasodilatory nervous activity in the central nervous system (CNS). Insulin may also mediate the vasodilatation by locally acting mechanisms in the skeletal muscle, which in turn could be modulated by vasoconstrictive sympathetic nervous activity. Five men with complete motoric lesions of their cervical spinal cord (SCI) and nine healthy (H) men underwent a hyperinsulinemic (480 mU x min(-1) x m(-2)), euglycemic clamp combined with arterio-venous catheterization of one leg and microdialysis of the thigh muscle. In response to hyperinsulinemia leg blood flow increased similarly in the two groups. Leg glucose extraction and uptake were significantly lower in SCI compared with H. Two hours post clamp, leg glucose uptake rates had not yet returned to basal values. Norepinephrine concentrations in arterial plasma and in the dialysate (reflecting extracellular fluid) did not change in response to insulin in either group, but increased in response to suprapubic bladder tapping in the SCI. Potassium balance measured by microdialysis shifted from a net release to a net uptake in response to insulin, with no difference between SCI and H. In conclusion, the mechanism by which insulin mediates an increase in skeletal muscle blood flow is not due to a CNS recruitment of sympathetic vasodilatory nervous activity. Nor is the insulin-mediated vasodilatation modulated by vasoconstrictive sympathetic nervous activity. The vasodilatation seen in response to hyperinsulinemia is a locally acting mechanism. People with SCI are markedly insulin resistant compared with able-bodied individuals.     

Human ageing and the sympathoadrenal system

Over the past three decades the changes in sympathoadrenal function that occur with age in healthy adult humans have been systematically studied using a combination of neurochemical, neurophysiological and haemodynamic experimental approaches. The available experimental evidence indicates that tonic whole-body sympathetic nervous system (SNS) activity increases with age. The elevations in SNS activity appear to be region specific, targeting skeletal muscle and the gut, but not obviously the kidney. The SNS tone of the heart is increased, although this appears to be due in part to reduced neuronal reuptake of noradrenaline (norepinephrine). In contrast to SNS activity, tonic adrenaline (epinephrine) secretion from the adrenal medulla is markedly reduced with age. This is not reflected in plasma adrenaline concentrations because of reduced plasma clearance. Despite widely held beliefs to the contrary, sympathoadrenal responsiveness to acute stress is not exaggerated with age in healthy adults. Indeed, adrenaline release in response to acute stress is substantially attenuated in older men. The mechanisms underlying the age-associated increases in SNS activity have not been established, but our preliminary data are consistent with increased subcortical central nervous system (CNS) sympathetic drive. These changes in sympathoadrenal function with advancing age may have a number of important physiological and pathophysiological consequences for human health and disease.     

Neuroaxonal dystrophy in aging human sympathetic ganglia.

Autonomic dysfunction is an increasingly recognized problem in aging animals and man. The pathologic changes that produce autonomic dysfunction in human aging are largely unknown; however, in experimental animal models specific pathologic changes have been found in selected sympathetic ganglia. To address whether similar neuropathologic changes occur in aging humans, the authors have examined paravertebral and prevertebral sympathetic ganglia from a series of 56 adult autopsied nondiabetic patients. They found significant, specific, age-related neuropathologic lesions in the prevertebral sympathetic superior mesenteric ganglia of autopsied patients. Markedly swollen dystrophic preterminal axons compressed or displaced the perikarya of principal sympathetic neurons. Ultrastructurally, these swollen presynaptic axons contained abundant disoriented neurofilaments surrounded by peripherally marginated dense core vesicles. Immunohistochemical studies demonstrated that dystrophic axons contained tyrosine hydroxylase and neuropeptide tyrosine (NPY)-like immunoreactivity but not other neuropeptides (VIP, substance P, gastrin-releasing peptide [GRP]/bombesin, met-enkephalin). Similar to the animal models of aging, lesions were much more frequent in the prevertebral superior mesenteric ganglia than in the paravertebral superior cervical ganglia. These studies demonstrate anatomic, peptidergic, and pathologic specificity in the aging human nervous system similar in many respects to that which the authors have described in experimental animal models. Neuroaxonal dystrophy in the sympathetic nervous system may underlie poorly understood alterations in clinical autonomic nervous system function that develop with age.     

Paraventricular nucleus of the hypothalamus and elevated sympathetic activity in heart failure: the altered inhibitory mechanisms

AIM: There is a characteristic neurohumoral activation in heart failure (HF). However, few studies have been performed to examine the role of the central nervous system in the activation of sympathetic outflow during HF. In this paper we review some of our studies, with particular emphasis on examining the role of the paraventricular nucleus (PVN) in the exaggerated sympathetic outflow commonly observed in HF. RESULTS: Our studies have revealed that the inhibitory mechanisms regulating sympathetic outflow are mediated by nitric oxide (NO) and gamma-aminobutyric acid (GABA) within the PVN and are attenuated in HF. These alterations are associated with elevated sympathetic activity. Furthermore, these studies have indicated that the interactions among excitatory (angiotensin II and glutamate) and inhibitory (NO and GABA) neurotransmitters/mediators within the PVN significantly influence sympathetic outflow. CONCLUSION: Reduced inhibitory actions of NO and/or GABA within the PVN may exaggerate an increase in the actions of excitatory neurotransmitters such as glutamate and angiotensin II within the PVN and this may contribute to the overall sympatho-excitation commonly observed in HF.     

Local and central sympathetic reflex control of blood flow in skeletal muscle and subcutaneous tissue in normal man

The effect of age and sex on relative changes in blood flow and vascular resistance in skeletal muscle and subcutaneous tissue during postural changes and during local increase in transmural pressure was studied in 33 healthy subjects. The intra-individual variation was studied in five subjects. Blood flow was measured by the local 133Xenon wash-out method. No relation to age or sex was seen in the centrally elicited sympathetic vasoconstrictor responses in subcutaneous tissue and skeletal muscle and in the locally elicited vasoconstriction in subcutaneous tissue. A small, but statistically significant, correlation to sex and age was found in the local sympathetic vasoconstrictor response in skeletal muscle. The age correlation was caused only by an attenuated response in the young subjects below 40 years of age and may be fortuitous. The intra-individual variation was acceptably small. Based on the present results, a reduction in blood flow in skeletal muscle and subcutaneous tissue during centrally or locally elicited sympathetic vasoconstriction of 10% or less should be considered abnormal. The local 133Xenon wash-out method is of value in examining patients suspected of dysfunction in the sympathetic part of the autonomic nervous system.     

Hypofunction of the sympathetic nervous system is an etiologic factor for a wide variety of chronic treatment-refractory pathologic disorders which all respond to therapy with sympathomimetic amines

The hypothesis set forth is that the basis for a great many chronic debilitating conditions that involve almost all of the physiologic systems of the body may have as the underlying cause and a common link between them, i.e., hypofunction of the sympathetic nervous system. The hypothesis considers that one of the main functions of the sympathetic nervous system is to diminish cellular permeability. Thus sympathetic hypofunction may lead to absorption of chemicals and toxins into tissues that were supposed to be impervious leading to inflammation and other adverse consequences which then cause a wide variety of symptoms. These symptoms may include pain or diminished muscular function leading to various pain syndromes or conditions related to diminished muscular function. Furthermore since the sympathetic nervous system is involved in body homeostasis and temperature regulation, sympathetic nervous system hypofunction could lead to disorders in these areas, e.g., vasomotor symptoms and edema. This defect in sympathetic nervous system has a genetic predisposition but relatives, e.g., siblings or children may manifest in a different manner which suggests some influence of external factors causing one physiological system to be more prone than another to malfunction under conditions of sympathetic hypofunction. Evidence to support this hypothesis has been provided by a large number of published anecdotes demonstrating the quick and long lasting considerable improvement in symptoms following treatment with the sympathomimetic amine dextroamphetamine sulfate (with return of symptoms if treatment is temporarily ceased thus diminishing the likelihood of spontaneous remission) despite failure to respond to a plethora of other pharmacologic agents and other therapies over many years. The physiological systems with various chronic disorders that have responded included the gastrointestinal system, skin, genitourinary system, the nervous system, the musculoskeletal system, the temperature regulation system, peripheral vasculature system, and the endocrine system. Despite the multitude of very convincing anecdotal reports showing its efficacy (and to date no reports refuting this hypothesis), there has only been one controlled study which showed the benefit of dextroamphetamine sulfate on edema and weight gain in diet-refractory patients. The flaw to date for general acceptance of this hypothesis is that most positive studies are coming from one clinical center. Furthermore, more controlled studies are needed. There has been a recent interest amongst physiologists and recent studies have been published confirming a deficiency of sympathetic nerve fibers in some of these disorders which hopefully will encourage more research into other physiologic systems leading to corroboration of this hypothesis.     

Sympathetic over activity in the etiology of hypertension of obstructive sleep apnea

Beginning with modest clinical observations in 1984, a picture has evolved suggesting that sympathetic nervous system over activity may be responsible in part for the elevated blood pressure seen in obstructive sleep apnea patients. Early studies of urinary and plasma catecholamines indirectly suggested sympathetic over activity carried to daytime, non-apneic conditions. Later intra-neuronal recordings of muscle sympathetic nerve activity directly demonstrated both acute and diumal (non-apneic) sympathetic over activity. Most importantly, diurnal sympathetic over activity has been shown to diminish with adequate treatment of apnea using nasal CPAP. Norepinephrine and angiotensin II are both released with increased peripheral sympathetic activity and are parallel vascular growth-promoting factors. Thus, one would expect alterations in vascular structure and function in a state of chronic sympathetic over activity. While changes in peripheral vascular structure have not been demonstrated in hypertension of sleep apnea, changes in peripheral vascular responsiveness have. There is reduced response to acetylcholine and isoproterenol vasodilation, and to norepinephrine and angiotensin vasoconstriction in humans with sleep apnea. Some of these vascular reactivity changes are shown to reversed with chronic nasal CPAP treatment. Finally, complimentary to the above evidence in humans, there is indirect evidence of sympathetic over activity as well as differences in vascular reactivity in intermittent hypoxia challenged rats. We have made significant strides in the past 15-20 years towards understanding systemic hypertension related to sleep apnea, especially the role of the sympathetic nervous system. Future research will need to look at exact mechanism of sympathetic nervous system over activity, particularly how central nervous system pathways may undergo facilitation, leading to daytime over activity. Furthermore, the mechanisms of sustained hypertension in sleep apnea patients is almost certainly of multiple etiologies. There is no marker for separating sleep apnea patients with hypertension derived solely from intermittent hypoxia from other secondary causes. Perhaps endothelial cell molecular markers could help to identify patients at risk for cardiovascular change associated with snoring and apnea, as well to guide treatment. Finally, studies demonstrating microvascular changes in blood vessels are extremely difficult to do, but promise to yield important knowledge about cellular mechanisms and results of long-term treatment of sleep apnea on cardiovascular disease.     

骨形态发生蛋白2与4在生长发育高峰期骨性Ⅱ类错牙合畸形中的表达

背景：课题组以往研究证实,骨形态发生蛋白4对生长发育期下颌骨的生长有促进作用,而骨形态发生蛋白2是否能与骨形态发生蛋白4相互促进下颌骨生长目前未见有相关报道。 目的：检测生长发育高峰期骨性Ⅱ类错牙合畸形患者血液中骨形态发生蛋白2和骨形态发生蛋白4的表达情况,以探究骨形态发生蛋白2和骨形态发生蛋白4的表达量与下颌骨生长的关系。 方法：生长发育高峰期骨性Ⅰ类错牙合畸形患者为Ⅰ组,以下颌后缩为主的骨性Ⅱ类错牙合畸形患者为Ⅱ组,每组18人。采用实时荧光定量PCR(RT-PCR)分别检测两组血液骨形态发生蛋白2和骨形态发生蛋白4的表达。 结果与结论：骨性Ⅱ类错牙合畸形组中骨形态发生蛋白2 mRNA的表达量明显低于对照组骨性Ⅰ类错牙合畸形组(P < 0.05),骨性Ⅱ类错牙合畸形组中骨形态发生蛋白4 mRNA的表达量明显低于对照组骨性Ⅰ类错牙合畸形组 (P < 0.05),骨性Ⅱ组中骨形态发生蛋白2与骨形态发生蛋白4的表达有显著相关性。结果证实,骨形态发生蛋白2和骨形态发生蛋白4在生长发育高峰期的表达量均降低与下颌骨发育不足有密切关系,且骨形态发生蛋白2和骨形态发生蛋白4相互协同,共同参与调节下颌骨的生长。     

The sympathetic nervous system in acute kidney injury

Acute kidney injury (AKI) is frequently accompanied by activation of the sympathetic nervous system (SNS). This may result from pre‐exisiting chronic diseases associated with sympathetic activation prior to AKI or it may be induced by stressors that ultimately lead to AKI such as endotoxins and arterial hypotension in circulatory shock. Conversely, sympathetic activation may also result from acute renal injury. Focusing on studies in experimental renal ischaemia and reperfusion (IR), this review summarizes the current knowledge on how the SNS is activated in IR‐induced AKI and on the consequences of sympathetic activation for the development of acute renal damage. Experimental studies show beneficial effects of sympathoinhibitory interventions on renal structure and function in response to IR. However, few clinical trials obtained in scenarios that correspond to experimental IR, namely major elective surgery, showed that peri‐operative treatment with centrally acting sympatholytics reduced the incidence of AKI. Apparently, discrepant findings on how sympathetic activation influences renal responses to acute IR‐induced injury are discussed and future areas of research in this field are identified.     

Identification of Sites of Sympathetic Outflow During Concurrent Recordings of Sympathetic Nerve Activity and fMRI

The sympathetic division of the nervous system is critical for maintaining both resting arterial pressure and for producing changes in regional perfusion required by behavioral state changes. A primary determinant of arterial pressure is the level of vasoconstriction within skeletal muscle. It is well established that there is a tight relationship between dynamic changes in arterial pressure and muscle sympathetic nerve activity (MSNA) through the workings of the baroreflex. While the central circuitry underlying the baroreflex has been extensively investigated in anesthetized experimental animals, few studies have investigated the central circuitry responsible for the baroreflex in awake human subjects. Recently we were the first to record concurrently MSNA (using microneurography) and brain activity (using functional magnetic resonance imaging) in awake humans in a series of experiments designed to determine the central circuitry underlying the baroreflex in humans. We confirmed that the baroreflex involves activity changes within the nucleus tractus solitarius, caudal ventrolateral, and rostral ventrolateral medulla. Because conditions such as essential hypertension, obesity, and obstructive sleep apnea are all characterized by significant increases in resting MSNA, it is important to understand both brainstem and cortical sites involved in regulating resting levels of MSNA. Future investigations which define cortical sites involved in generating and modulating MSNA are important if we are to understand the underlying mechanisms of many conditions characterized by hypertension. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

Innervation of immune cells: evidence for neuroimmunomodulation in the liver

Recent studies have demonstrated a pronounced influence by the autonomic nervous system on immune-mediated experimental hepatitis in the mouse. Adrenergic sympathetic neurons alleviate while capsaicin-sensitive peptidergic primary afferent neurons aggravate liver injury. This was evidenced by recording morphological and functional parameters upon chemical sympathectomy and application of beta-adrenergic agonists, and capsaicin depletion of afferents, neurokinin receptor antagonists, and application of exogenous substance P, respectively. These phenomena are most likely based on close anatomical relationships between nerve fibers and various immune cells in the liver. Modulation of autonomic nervous system functions may open novel therapeutic strategies in immune and inflammatory liver diseases.     

Any beneficial effects of mycobacteria on multiple sclerosis and experimental autoimmune encephalitis may include stimulation of the sympathetic nervous system

The inhibitory effects of mycobacterial infection and mycobacterium components on multiple sclerosis (MS) and experimental autoimmune encephalitis (EAE; an animal model for MS) have been known for years. However, this effect seems like a paradox that both mycobacterial infection and MS induce type I immune responses. Some mechanisms have been proposed or even proven for this effect in different studies, but among them there is no hint of a possible role for the nervous system (NS). Regarding the close relations between sympathetic nervous system (SNS) and MS disease course, it can be hypothesized that SNS may have a role in the effects of mycobacterium on MS. Hypothesis: SNS can be stimulated by pro-inflammatory cytokines such as TNF-alpha and IL1-beta, production of which are induced by mycobacterial infection or mycobacterium components. Although these cytokines can inhibit SNS in the site of inflammation caused by mycobacterium, they increase sympathetic tone in other places. The beneficial role of SNS in inhibiting or attenuating the course of MS and EAE has been suggested. Inhibitory effects of stimulated SNS on MS may occur via different ways such as inhibiting the production of pro-inflammatory cytokines and inducing the synthesis of anti-inflammatory cytokines, in other words, shifting the immune responses from type 1 toward type 2, as well as, induction of suppressor/regulator T lymphocytes, induction of heat shock proteins in brain and increasing the expression of Fas and Fas-ligand. Therefore, it seems that stimulation of SNS by mycobacterial infection or mycobacterium components is a key step in the mechanism of beneficial effects of mycobacterium on MS.     

Bone mass regulation by leptin: a hypothalamic control of bone formation

Bone mass is maintained constant between puberty and menopause by the balance between osteoblasts and osteoclasts activity. The existence of a hormonal control of osteoblast activity has been speculated for years by analogy to osteoclast biology. Through the search for such humoral signal(s) regulating bone formation, leptin has been identified as a powerful inhibitor of bone formation. Furthermore, by means of intracerebroventricular infusion of leptin, it has been shown that the effect of this adipocyte-derived hormone on bone is mediated via a brain relay, like all its other functions. Subsequent studies have led to the identification of hypothalamic neurons involved in leptin's antiosteogenic function. In addition, it has been shown that those neurons or neuronal pathways are distinct from neurons responsible for the regulation of energy metabolism. Finally, the peripheral mediator of leptin's antiosteogenic function has been identified as being the sympathetic nervous system. Catecholamine-deficient mice have a high bone mass and sympathomimetics administered to mice decreased bone formation and bone mass. Conversely, beta-blockers increased bone formation and bone mass and blunt the bone loss induced by ovariectomy.     

Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur

Although skeletal pain plays a major role in reducing the quality of life in patients suffering from osteoarthritis, Paget's disease, sickle cell anemia and bone cancer, little is known about the mechanisms that generate and maintain this pain. To define the peripheral fibers involved in transmitting and modulating skeletal pain, we used immunohistochemistry with antigen retrieval, confocal microscopy and three-dimensional image reconstruction of the bone to examine the sensory and sympathetic innervation of mineralized bone, bone marrow and periosteum of the normal mouse femur. Thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP) and the unmyelinated, non-peptidergic sensory fibers were labeled with the isolectin B4 (Bandeira simplicifolia). Myelinated sensory fibers were labeled with an antibody raised against 200-kDa neurofilament H (clone RT-97). Sympathetic fibers were labeled with an antibody raised against tyrosine hydroxylase. CGRP, RT-97, and tyrosine hydroxylase immunoreactive fibers, but not isolectin B4 positive fibers, were present throughout the bone marrow, mineralized bone and the periosteum. While the periosteum is the most densely innervated tissue, when the total volume of each tissue is considered, the bone marrow receives the greatest total number of sensory and sympathetic fibers followed by mineralized bone and then periosteum.Understanding the sensory and sympathetic innervation of bone should provide a better understanding of the mechanisms that drive bone pain and aid in developing therapeutic strategies for treating skeletal pain.