Central control of bone remodeling

The hormonal control of osteoblast activity has been speculated for a long time. In search of such a central hormone, leptin was identified as an inhibitor of bone formation. Intracerebroventricular infusion of leptin resulted in a decrease of bone mass establishing that bone mass is regulated centrally. The peripheral mediator of leptin’s action was identified as being the sympathetic nervous system. Mice deficient for catecholamines have high bone mass. β-Receptor agonists decreased bone mass, and conversely, treatment by β-blockers increased bone mass.     

Central effects of neuromedin U in the regulation of energy homeostasis

Neuromedin U (NMU) is a brain-gut peptide whose peripheral activities are well-understood but whose central actions have yet to be clarified. The recent identification of two NMU receptors in rat brain has provided a springboard for further investigation into its role in the central nervous system. Intracerebroventricular administration of NMU to free-feeding rats decreased food intake and body weight. Conversely, NMU increased gross locomotor activity, body temperature, and heat production. NMU, a potent endogenous anorectic peptide, serves as a catabolic signaling molecule in the brain. Further investigation of the biochemical and physiological functions of NMU will help our better understanding of the mechanisms of energy homeostasis.     

The control of bone remodeling by neuropeptide Y receptors

An important role for the neuropeptide Y receptor system in the regulation of bone formation was recently revealed with a significant elevation in trabecular bone formation and bone volume following germline or hypothalamus-specific deletion of neuropeptide Y2 receptors in mice. Subsequent studies have now demonstrated that this central pathway is distinct from that of the other centrally regulated bone formation pathway mediated by leptin. This review discusses these recent findings and outlines how these new pathways could translate into potential novel targets for the treatment of bone disease.     

Regulation of gonadotropin secretion and puberty onset by neuromedin U

Neuromedin U (NMU), an anorexigenic peptide, was originally isolated from porcine spinal cord in 1985. As NMU is abundant in the anterior pituitary gland, we investigated the effects of NMU on gonadotropin secretion. Both NMU and its receptors, NMUR1 and NMUR2, were expressed in the pituitary gland. NMU suppressed LH and FSH releases from rat anterior pituitary cells. Moreover, NMU-deficient mice exhibit an early onset of vaginal opening. The LHbeta/FSHbeta ratio, which is an index of puberty onset, is high in young NMU-deficient mice. These results indicate that NMU suppresses gonadotropin secretion and regulates the onset of puberty.     

The neuropeptide neuromedin U promotes autoantibody-mediated arthritis

Introduction  

Neuromedin U (NMU) is a neuropeptide with pro-inflammatory activity. The primary goal of this study was to determine if NMU promotes autoantibody-induced arthritis. Additional studies addressed the cellular source of NMU and sought to define the NMU receptor responsible for its pro-inflammatory effects.     

Isolation and structural determination of rat neuromedin U

Rat neuromedin U was isolated from the small intestine using mainly immunoaffinity chromatography and radioimmunoassay for pig neuromedin U-8. The amino acid sequence of rat neuromedin U was determined by microsequence analysis to be Tyr-Lys-Val-Asn-Glu-Tyr-Gln-Gly-Pro-Val-Ala-Pro-Ser-Gly-Gly- Phe-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2, and this structure was confirmed by synthesis. Although the C-terminal heptapeptide amide structure of pig neuromedin U is completely conserved in rat neuromedin U, the remainder of the peptide reveals nine amino acid replacements and two amino acid deletions when compared to pig neuromedin U-25. Rat neuromedin U exerts two-fold potent uterus stimulant activity as compared to pig neuromedin U-25.     

Cloning and characterization of murine neuromedin U receptors

Neuromedin U (NmU) is a neuropeptide involved in various physiological functions such as feeding behavior, muscle contractile activity, and regulation of intestinal ion transport. Recently, two human G protein-coupled receptors have been identified as NmU-specific receptors, NmU-R1 and NmU-R2, which share 55% amino acid identity. It is unclear however, which of the two receptors mediates responses to NmU observed in rodent models. Attempts to define the pharmacological profile of the two receptors are confounded by overlapping expression of the two receptors and a lack of subtype-selective compounds. In order to establish a basis to further our understanding of the function of these receptors, we cloned and characterized the mouse homologues of the two human NmU receptors. Mouse NmU-R1 and mouse NmU-R2 are 79 and 81% identical to their respective human homologues. Expression of NmU-R1 was mainly observed in testis, gastrointestinal (GI) tract, and immune system, while NmU-R2 was primarily expressed in brain tissues. Each mouse receptor was independently expressed in HEK293 cells and demonstrated a dose-dependent calcium flux in response to NmU-8, NmU-23 and NmU-25. In an attempt to identify a synthetic NmU peptide that would exhibit selectivity at one of the two receptors, we examined the functional activity of eight alanine-substituted NmU-8 peptides. These experiments demonstrated that alanine substitution at positions 5 and 7 affects the functional activity of the peptide at both receptors. The arginine residue at position 7 is required for NmU-8 activity at either receptor while alanine substitution at position 5 selectively affects the potency and the efficacy at mNmU-R1. These experiments validate the use of rodent models to characterize NmU function relative to humans and suggest that substitution at Arginine-5 of NmU-8 may provide a receptor selective peptide.     

Cardiovascular actions of central neuromedin U in conscious rats

Neuromedin U (NMU) is a brain-gut peptide, which peripherally stimulates smooth muscle, increases of blood pressure, alters ion transport in the gut, controls local blood flow, and regulates adrenocortical function. Although intracerebroventricular (i.c.v.) administration of NMU is known to decrease food intake and body weight, little is known about its effect on other physiological functions. We examined the effects of i.c.v. administration of NMU on mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine in conscious rats. Neuromedin U (0.05 and 0.5 nmol) provoked an increase in MAP (93.8 +/- 0.5 to 123.5 +/- 1.7 and 94.7 +/- 0.8 to 132.7 +/- 3.0 mm Hg, respectively) and HR (334.9 +/- 6.0 to 494.1 +/- 6.9 and 346.3 +/- 3.3 to 475.1 +/- 8.9 beats/min, respectively). In contrast, plasma norepinephrine increased only with a high dose of neuromedin U. Intravenously administered NMU (0.5 nmol) elicited a small and short lasting increase in MAP, compared to that by i.c.v. NMU. These results indicate that central neuromedin U regulates sympathetic nervous system activity and affects cardiovascular function.     

Role of innervation in the control of bone remodeling

During the last fifteen years, an increasing number of studies have examined the origin, the ontogeny, and the distribution of nerve fibers in bone. They have also investigated the nature of neuromediators conveyed by these skeletal nerve fibers. Experimental models of sensory and sympathetic denervation and clinical studies have shown that these two neuronal systems are involved in bone development, growth and remodeling. More recently, some new concepts regarding the role of nerve fibers in bone physiology have emerged with the demonstration of a leptin-dependent central control of bone formation via the sympathetic system. This new neural regulating pathway of bone cell functions could have enormous implications for human skeletal biology and treatment of bone pathologies.     

A potent neuromedin U receptor 2-selective alkylated peptide

Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe¹⁹, Nle²¹, and Arg(Me)²⁴] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU.     

A role for neuromedin U in stress response.

Neuromedin U (NMU) is a hypothalamic peptide that has been recently found to reduce food intake, but few is known about its other functions in the central nervous system. We here studied behavioral activities induced by an intracerebroventricular (ICV) administration of NMU in rats and mice. NMU increased gross locomotor activity, face washing behavior, and grooming. NMU-induced stress response was significantly abolished by pretreatment with an antagonist of corticotropin-releasing hormone (CRH), alpha-helical CRH (9-41) (alpha-hCRH), or anti-CRH IgG. NMU did not induce locomotor activity in CRH knockout mice. NMU that interacts anatomically and/or functionally with the CRH system is a novel physiological regulator of stress response.     

瘦素对骨重建的神经调节

骨重建是骨骼保持自我更新的过程,以往认为骨重建的调节仅涉及骨骼局部的自分泌、旁分泌等方式。近年来的研究发现,中枢神经系统对骨重建的维持发挥关键作用,瘦素是其中重要的调控因子。本文简要综述瘦素通过交感神经系统、神经肽(可卡因安非他明调节转录肽,CART),以及神经介素U对骨重建的调节作用及其分子基础。     

Novel role of the anorexigenic peptide neuromedin U in the control of LH secretion and its regulation by gonadal hormones and photoperiod

Neuromedin U (NMU) is a widely spread neuropeptide, with predominant expression at the gastrointestinal tract and brain, putatively involved in the regulation of a diversity of biological functions, including food intake, energy balance and circadian rhythms; all closely related to reproduction. Yet, the implication of NMU in the control of the gonadotropic axis remains scarcely studied. We report herein analyses on the hypothalamic expression and function of NMU in different physiological and experimental states of the rat reproductive system. Expression of NMU mRNA at the hypothalamus was persistently detected along female postnatal development, with maximum levels in adulthood that fluctuated across the cycle and were modulated by ovarian steroids. Acute central administration of NMU evoked increases of serum LH levels in pubertal female rats, while repeated injection of NMU tended to advance vaginal opening. Likewise, central injection of NMU increased serum LH concentrations in cycling female rats, with peak responses in estrus. In contrast, NMU significantly inhibited preelevated LH secretion in gonadectomized and kisspeptin-treated rats. Finally, in noncycling females due to photoperiodic manipulation (constant light), hypothalamic NMU mRNA levels were markedly depressed, but relative LH responses to exogenous NMU were significantly augmented. All together, our present data support a predominant stimulatory role of NMU in the control of the female gonadotropic axis, which appears under the influence of developmental, hormonal, and photoperiodic cues, and might contribute to the joint regulation of energy balance, biological rhythms, and reproduction.     

Isolation, structural characterization and pharmacological activity of dog neuromedin U

The neuromedin U-like immunoreactivity in an extract of dog small intestine was resolved by reversed-phase HPLC into two molecular forms. The primary structure of the larger form (NMU-25) was established as: Phe-Arg-Leu-Asp-Glu-Glu-Phe-Gln-Gly-Pro10-Ile-Ala-Ser-Gln-Val-Arg- Arg-Gln-Phe- Leu20-Phe-Arg-Pro-Arg-Asn-NH2. This sequence shows five substitutions relative to pig neuromedin U-25. The primary structure of the second peptide (NMU-8) was established as: pGlu-Phe-Leu-Phe-Arg-Pro-Arg-Asn-NH2. The sequence contains the substitution pGlu for Tyr1 compared with pig neuromedin U-8. The potency of synthetic dog NMU-8 in contracting smooth muscle from the rat uterus (EC50 10 +/- 2 nM; mean +/- S.E., n = 6) was not significantly different from the corresponding potency of pig NMU-8 (EC50 16 +/- 5 nM) but the maximum response produced by the dog peptide was greater (58%; p less than 0.05) than that produced by pig NMU-8.     

Mandibular bone remodeling induced by dental implant

The ability to assess the effects of an implant on bone remodeling is of particular importance to prosthesis placement planning and associated treatment assurance. Prediction of on-going bone responses will enable us to improve the performance of a restoration. Although the bone remodeling for long bones had been extensively studied, there have been relatively few reports for dental scenarios despite its increasing significance with more and more dental implant placements. This paper aimed to develop a systematic protocol to assess mandibular bone remodeling induced by dental implantation, which extends the remodeling algorithms established for the long bones into dental settings. In this study, a 3D model for a segment of a human mandible was generated from in vivo CT scan images, together with a titanium implant embedded to the mandible. The results examined the changes in bone density and stiffness as a result of bone remodeling over a period of 48 months. Resonance frequency analysis was also performed to relate natural frequencies to bone remodeling. The density contours are qualitatively compared with clinical follow-up X-ray images, thereby providing validity for the bone remodeling algorithm presented in dental bone analysis.     

Periosteal and endosteal control of bone remodeling under torsional loading.

The shape changes that occur in the mid-diaphysis of a long bone due to adaptive remodeling induced by increasing or decreasing the axial and/or torsional loading of the bone are investigated using a simple model. In this model the mid-diaphysis of a long bone is represented as a hollow thick-walled right-circular cylinder, and different optimal strategies for bone remodeling are considered. It is shown that if such a thick-walled right-circular cylinder capable of surface remodeling is subjected to an axial compressive load and a twisting torque, then the remodeling patterns depend on whether the periosteal surface or the endosteal surface controls the limits of the remodeling process. It is shown that the effect of increasing the torque is always opposite to the effect of increasing the compressive load. Thus, similar remodeling patterns are obtained by increasing one type of loading and decreasing the other. Aside from the restriction of idealized cylindrical geometry, the only assumptions made are that the bone tissue is linearly elastic and that there exists a finite range of remodeling equilibrium stresses. Only those loading situations which maintain the bone in remodeling equilibrium are considered in this work. It follows that the results presented are independent of the specific type of rule governing the temporal evolution of the bone shape, since any such rule applies only in situations where there is active remodeling and, hence, no remodeling equilibrium.     

Characterization of complementary DNA encoding the rat neuromedin U precursor.

Neuromedin U (NmU), a peptide originally isolated from porcine spinal cord, is known for its ability to stimulate uterine smooth muscle contraction and to cause selective vasoconstriction. It was subsequently isolated from a number of species. Among the species studied, the five amino acids at the C-terminus of the peptide are totally conserved, suggesting that this region is of major importance. We have cloned and sequenced the cDNA encoding the rat NmU precursor protein using the anchor polymerase chain reaction technique. Sequence analysis revealed that NmU is synthesized as a 174-amino acid precursor. Like the precursors of most other small regulatory peptides, it has a hydrophobic signal peptide and a number of paired dibasic amino acids, which may serve as signals for enzymatic cleavage, to release NmU and a series of other peptides. These predicted flanking peptides of NmU show no significant homology with entries in the protein databases searched, and the cDNA likewise shows no homology with entries in the GenBank database. Northern blot analysis using total RNA extracted from different rat tissues shows high levels of NmU mRNA in the ileum, thyroid, and anterior pituitary. Southern blot analysis of rat genomic DNA demonstrates that NmU is a single copy gene.