Moderate osteoporosis itself is beneficial for bones.
Xiong Zhonghua,Wu Jiayu,Liu Zhenjun,Jing Wei
There have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis. A typical example is medication-related osteonecrosis of the jaws (MRONJ) which can cause massive necrosis and defects of the jaws. Thus, the dosage and effects of anti-osteoporosis drugs should be re-examined. Our hypothesis is that primary moderate osteoporosis itself is beneficial for bones and should not be excessively treated other than vitamin D, calcium supplementation and functional exercises. The self-repair and anti-infection abilities of bone depend on its organic tissues including stem cells, blood vessels, osteoclastic and osteogenic factors in bone, which jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in senescent cell numbers. Thus, the number of MSCs and vessels need to be increased to achieve functions similar to those in young people. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair. Moreover, long term use of anti-osteoporosis drugs also have negative effects on long bones and cartilages. Therefore, moderate age-related osteoporosis is natural in humans to protect bones. Excessive treatment of osteoporosis weakens immunity and self-repair.
Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.
Stark Romana,Reichenbach Alex,Andrews Zane B
Molecular and cellular endocrinology
The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin at POMC or NPY neurons may depend on appropriate nutrient-sensing in these neurons and we hypothesize carnitine metabolism is critical in the integrative processing. Future research is required to examine the neuron-specific effects of carnitine metabolism on concurrent nutrient- and hormonal-sensing in AgRP and POMC neurons.
The brain in bone and fuel metabolism.
Wee Natalie K Y,Kulkarni Rishikesh N,Horsnell Harry,Baldock Paul A
Obesity and osteoporosis have become major public health challenges worldwide. The brain is well established as a pivotal regulator of energy homeostasis, appetite and fuel metabolism. However, there is now clear evidence for regulation between the brain and bone. Similarly, evidence also indicates that the involvement of the brain in bone and adipose regulation is both related and interdependent. The hypothalamus, with its semi-permeable blood brain barrier, is one of the most powerful regulatory regions within the body, integrating and relaying signals not only from peripheral tissues but also from within the brain itself. Two main neuronal populations within the arcuate nucleus of the hypothalamus regulate energy homeostasis: The orexigenic, appetite-stimulating neurons that co-express neuropeptide Y and agouti-related peptide and the anorexigenic, appetite-suppressing neurons that co-express proopiomelanocortin and cocaine- and amphetamine related transcript. From within the arcuate, these four neuropeptides encompass some of the most powerful control of energy homeostasis in the entire body. Moreover, they also regulate skeletal homeostasis, identifying a co-ordination network linking the processes of bone and energy homeostasis. Excitingly, the number of central neuropeptides and neural factors known to regulate bone and energy homeostasis continues to grow, with cannabinoid receptors and semaphorins also involved in bone homeostasis. These neuronal pathways represent a growing area of research that is identifying novel regulatory axes between the brain and the bone, and links with other homeostatic networks; thereby revealing a far more complex, and interdependent bone biology than previously envisioned. This review examines the current understanding of the central regulation of bone and energy metabolism.
Leptin-dependent co-regulation of bone and energy metabolism.
Yadav Vijay K,Karsenty Gerard
The adipocyte-derived hormone leptin inhibits appetite and bone mass accrual. To fulfill these two functions leptin requires the integrity of hypothalamic neurons but not the expression of its receptor, ObRb on these neurons. These results suggested that leptin acts first elsewhere in the brain to mediate these functions. However, this neuroanatomical site of leptin action in the brain remained elusive. Recent mouse genetic, electrophysiological and neuroanatomical studies provide evidence that leptin inhibits appetite and bone mass accrual through a two-step pathway: it decreases synthesis and the release by brainstem neurons of serotonin that in turn targets hypothalamic neurons to regulate appetite and bone mass accrual.
The new field of neuroskeletal biology.
Patel M S,Elefteriou F
Calcified tissue international
The fields of neuroscience and bone biology have recently converged following the discovery that bone remodeling is directly regulated by the brain. This work has defined bone remodeling as one of the cardinal physiological functions of the body, subject to homeostatic regulation and integrated with the other major physiological functions by the hypothalamus. Central to this discovery was the definition of the adipocyte-derived hormone leptin as a regulator of both arms of bone remodeling, formation and resorption, through its action on the ventromedial hypothalamus and subsequently via the sympathetic nervous system to osteoblasts. The characterization of the sympathetic nervous system as a regulator of bone remodeling has led to several large clinical studies demonstrating a substantial protective effect of beta-blockers, particularly beta1-blockers, on fracture risk. Studies in model organisms have reinforced the role of the central nervous system in the regulation of bone remodeling in vivo by the identification of several additional genes, namely cocaine and amphetamine regulated transcript (Cart), melanocortin 4 receptor (Mc4R), neuropeptide Y (NPY), Y2 receptor, cannabinoid receptor CB1 (Cnbr1), and the genes of the circadian clock. These genes have several common features, including high levels of expression in the hypothalamus and the ability to regulate other major physiological functions in addition to bone remodeling including energy homeostasis, body weight, and reproduction. We review the major pathways that define the new field of neuroskeletal biology and identify further avenues of inquiry.
Shen (Kidney)-tonifying principle for primary osteoporosis: to treat both the disease and the Chinese medicine syndrome.
Shu Bing,Shi Qi,Wang Yong-jun
Chinese journal of integrative medicine
Primary osteoporosis (POP) is one of the most common diseases in the elderly people resulting in high risk of fracture and poor quality of life. In addition to the pathological changes in bone mass, most of the POP patients also suffer from Chinese medicine (CM) syndromes of Shen (Kidney) essence deficiency. Shen essences are highly related to bone. Shen essence deficiency plays an important part in the development of POP and a better diagnosis of POP could be made by combining CM syndromes with Western medicine risk factors. Treatments of POP should aim at both increasing the bone mass and relieving the syndromes of Shen essence deficiency. Clinical study confirmed that treating POP patients with Shen-tonifying herbs could increase the bone mass and relieve the CM syndromes of POP patients. Basic researches clarified the mechanism by which Shen-tonifying herbs increased bone mass in animal models. The mechanisms by which Shentonifying herbs relieve the CM syndromes are still in investigation.
Mechanisms of "kidney governing bones" theory in traditional Chinese medicine.
Ju Dahong,Liu Meijie,Zhao Hongyan,Wang Jun
Frontiers of medicine
Studies conducted by our group on the mechanism of "kidney governing bones" theory in traditional Chinese medicine (TCM) are reviewed in this paper. Conclusions can be summarized as follows. (1) Neuroendocrine-immune network (NIN)-osteoclast regulatory pathway OPG-RANKL-RANK is one of the mechanisms of "kidney governing bones." Although kidney-reinforcing therapy is regarded as one of the holistic regulatory mechanisms of the body, characteristic holistic regulation in TCM can be reflected through nonselective regulation of the NIN during kidney reinforcement therapy, which can be used to treat osteoporosis through microadjustments in the microenvironment of the bone marrow. (2) Marrow exhaustion in TCM, which is the state wherein lipocytes in the bone marrow increase whereas other cells decrease, serves as the pathogenesis of osteoporosis brought about by failure of the "kidney governing bones." (3) The kidney in TCM can be regarded as a complex system comprising multiple functional units in the body, including the unit "governing bones." Kidney deficiency refers to a deficiency in only one or more units of the kidney system and not the whole system itself, which explains the kidney-reinforcing effect of many herbs; some herbs can treat osteoporosis, but some cannot. Although both classified as kidney-reinforcing agents, the former can resolve failure of the "kidney governing bones" unit while the latter regulates the failure of other units in the kidney system. Despite the current understanding on "kidney governing bones" theory, the mechanism of "kidney governing bones" remains complicated and unresolved. Thus, further studies in this area are warranted.
[Research progress on anti-osteoporotic active ingredients and pharmacological action mechanism of traditional Chinese kidney-tonifying and bone-strengthening drugs].
Li Ye,Tong Jie,Zhou Yan-jing,Xu Xiao-yu
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
The therapeutic effects and mechanisms of traditional Chinese kidney-tonifying drugs in treating osteoporosis have become the focus under study. Pharmacological studies have shown that traditional Chinese kidney-tonifying drugs are promoters for the proliferation of osteoblasts, inhibitors for the activity of osteoclasts, regulators for the estrogen level and its receptor, plays important roles in promoting osteogenesis and suppressing adipogenesis of marrow mesenchymal stem cells (MSCs), modulating the function of OPG/RANK/RANKL system and the metabolism of calcium and phosphorus, as well as antioxidation. The anti-osteoporotic active ingredients and pharmacological action mechanism of traditional Chinese kidney-tonifying drugs are summarized from the perspective of molecular and cell biology in this paper, so as to provide references for the study of their mechanism of anti-osteoporosis and for the development of traditional Chinese kidney-tonifying and bone-strengthening drugs.
Effects of water extract from epimedium on neuropeptide signaling in an ovariectomized osteoporosis rat model.
Liu Hengrui,Xiong Yingquan,Wang Haixia,Yang Li,Wang Chaopeng,Liu Xiaoguang,Wu Zhidi,Li Xiaoyun,Ou Ling,Zhang Ronghua,Zhu Xiaofeng
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:For the past millennium, water extract from Epimedium (dried leaves of Epimedium brevicornu Maxim.) has been widely used for bone disease therapy in traditional Chinese medicine and has been reported to exhibit salutary effects on osteoporosis in clinical trials. The therapeutic effect of Epimedium is associated with the function of the brain in traditional Chinese medicine theory. STUDY AIM:To determine the potential relationship between treating osteoporosis with Epimedium and neuropeptide regulation. MATERIALS AND METHODS:Water extract from Epimedium was qualitatively and quantitatively analyzed with HPLC-TOF-MS. Ovariectomized rats were used as an osteoporosis model and were treated orally with water extract from Epimedium 16 weeks after surgery to mimic clinical therapy. After treatment, gene expression and protein levels of four neuropeptides, as well as their main receptors or receptor precursors including; neuropeptide Y (NPY) and its receptors NPY 1 (NPYR1) and 2; calcitonin gene-related peptide and its receptor precursor calcitonin receptor-like receptor (CRLR); vasoactive intestinal peptide (VIP) and its receptor VIP 1 (VIP1R) and 2; and substance P (SP) and its receptor neurokinin 1 receptor (NK1R) were detected in samples taken from bone, brain and spinal cord. RESULTS:Treatment with water extract from Epimedium prevented bone mineral loss and reduced femoral bone strength decline associated with osteoporosis. Detection of neuropeptides showed that treatment also affected neuropeptide in the brain/spinal cord/bone axis; specifically, treatment increased brain NPY, bone NPY1R, bone CRLR, bone and spinal cord VIP and VIP2R, bone SP, and brain and spinal cord NK1R. CONCLUSION:The effects of osteoporosis can largely be reduced by treatment with Epimedium most likely through a mechanism associated with several neuropeptides involved in regulation of the brain/spinal cord/bone axis. These novel results contribute to existing literature regarding the possible mechanisms of habitual use of Epimedium in the treatment of osteoporosis.
Mechanism of Treatment of Kidney Deficiency and Osteoporosis is Similar by Traditional Chinese Medicine.
Wang Su-Juan,Yue Wei,Rahman Khalid,Xin Hai-Liang,Zhang Qiao-Yan,Qin Lu-Ping,Zhang Hong
Current pharmaceutical design
Traditional Chinese medicine (TCM) is a theoretical based system and is completely different from western medicine and states that numerous diseases, especially chronic diseases, are cured or relieved. "Zheng" (syndrome) is a summarization of the pathological changes which take place during the different stages of the development of a disease, including its location, cause and nature as well as the state of both Xie-qi (pathogenic factors) and Zheng-qi (healthy energy). Compared to a single symptom, syndrome can demonstrate the nature of a disease more extensively, completely and correctly. However, it is difficult to compare "Zheng" to the western medicine theory, which is based on scientific evidence for the diagnosis and treatment of a specific disease. Estrogen deficiency is a major pathogenetic factor in bone loss after menopause and oophorectomy with the subsequent risk of developing osteoporosis. According to TCM theory, the kidney stores essence and this can transform into bone marrow to nourish the bones, strenghthen the skeleton by promoting growth and repair. The kidney deficiency can decrease the estrogen level adjusted by the gonadal axis, causing osteoporosis. Traditional Chinese medicines tonifying the kidney can significantly enhance the level of estrogen to alleviate osteoporosis. In combination with other evidence, we further deduce that the syndrome as defined within TCM has a similar pathological mechanism to that defined by western medicine. If TCM theory is to be understood and accepted, and further fused with the western medicine theory, the micro pathological basis of TCM syndrome must be investigated extensively, which will lead to bridging the two theories together. The fusion of TCM with western medicine will pay more attention to analyzing the common nature and difference of disease and syndrome. This paper reviews the way forward for new translational advances.
Chronic Psychological Stress as a Risk Factor of Osteoporosis.
Azuma Kagaku,Adachi Yasuhiro,Hayashi Haruki,Kubo Kin-Ya
Journal of UOEH
Osteoporosis, the most common metabolic skeletal disease, is characterized by decreased bone mass and deteriorated bone quality, leading to increased fracture risk. With the aging of the population, osteoporotic fracture is an important public health issue. Organisms are constantly exposed to various stressful stimuli that affect physiological processes. Recent studies showed that chronic psychological stress is a risk factor for osteoporosis by various signaling pathways. The purpose of this article is to review the recent progress of the association between chronic psychological stress and osteoporosis. Increasing evidence confirms the physiological importance of the central nervous system, especially the hypothalamus, in the regulation of bone metabolism. Both animal and human studies indicate that chronic psychological stress induces a decrease of bone mass and deterioration of bone quality by influencing the hypothalamic-pituitary-adrenocortical (HPA) axis, sympathetic nervous system, and other endocrine, immune factors. Active mastication, proven to be an effective stress-coping behavior, can attenuate stress-induced neuroendocrine responses and ameliorate stress-induced bone loss. Therefore, active mastication may represent a useful approach in preventing and/or treating chronic stress-associated osteoporosis. We also discuss several potential mechanisms involved in the interaction between chronic stress, mastication and osteoporosis. Chronic stress activates the HPA axis and sympathetic nervous system, suppresses the secretion of gonadal hormone and growth hormone, and increases inflammatory cytokines, eventually leading to bone loss by inhibiting bone formation and stimulating bone resorption.
Cortisol secretion, bone health, and bone loss: a cross-sectional and prospective study in normal non-osteoporotic women in the early postmenopausal period.
Osella Giangiacomo,Ventura Massimo,Ardito Arianna,Allasino Barbara,Termine Angela,Saba Laura,Vitetta Rosetta,Terzolo Massimo,Angeli Alberto
European journal of endocrinology
OBJECTIVE:The aim of the study was to evaluate the relationship between cortisol secretion, bone health, and bone loss in a cohort of normal women in the early postmenopausal period. METHODS:We measured lumbar and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and heel ultrasound parameters in 82 healthy, nonosteoporotic (lumbar T-score ≥-2.0) women (median age 52.5 years, range 42-61). These women were examined in two sessions, 1 year apart, in the early postmenopausal period (onset of menopause between 6 and 60 months). Parameters of the hypothalamic-pituitary-adrenal (HPA) axis function were morning serum cortisol, morning and midnight salivary cortisol, 24-h urinary free cortisol (UFC), serum cortisol after 0.5 and 1 mg overnight dexamethasone, and DHEA-S. RESULTS:In multiple regression analyses, the following significant inverse correlations were found: i) lumbar BMD and either 24-h UFC (P<0.005) or morning serum cortisol (P<0.05), ii) total femur and femoral neck BMD with morning serum cortisol (P=0.05 and P<0.05), and iii) heel ultrasound stiffness index and midnight salivary cortisol (P<0.005). The annual rate of change in lumbar and femoral BMD did not correlate with any of the above-mentioned hormonal variables. No difference was found in the parameters of HPA axis function in slow (loss of BMD <1%) vs fast (loss of BMD ≥3%) bone losers. CONCLUSIONS:HPA axis may contribute to postmenopausal bone health, but differences in cortisol secretion do not influence the differential rate of bone loss between slow and fast bone losers in the early postmenopausal period, at least in healthy women.
Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic-pituitary disconnection (HPD).
Bindl Ronny,Oheim Ralf,Pogoda Pia,Beil Frank Timo,Gruchenberg Katharina,Reitmaier Sandra,Wehner Tim,Calcia Enrico,Radermacher Peter,Claes Lutz,Amling Michael,Ignatius Anita
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
We recently established a large animal model of osteoporosis in sheep using hypothalamic-pituitary disconnection (HPD). As central regulation is important for bone metabolism, HPD-sheep develop severe osteoporosis because of low bone turnover. In this study we investigated metaphyseal fracture healing in HPD-sheep. To elucidate potential pathomechanisms, we included a treatment group receiving thyroxine T4 and 17β-estradiol. Because clinically osteoporotic fractures often occur in the bone metaphysis, HPD-sheep and healthy controls received an osteotomy in the distal femoral condyle. Half of the HPD-sheep were systemically treated with thyroxine T4 and 17β-estradiol during the healing period. Fracture healing was evaluated after 8 weeks using pQCT, µCT, and histomorphometrical analysis. Bone mineral density (BMD) and bone volume/total volume (BV/TV) were considerably reduced by 30% and 36%, respectively, in the osteotomy gap of the HPD-sheep compared to healthy sheep. Histomorphometry also revealed a decreased amount of newly formed bone (-29%) and some remaining cartilage in the HPD-group, suggesting that HPD disturbed fracture healing. Thyroxine T4 and 17β-estradiol substitution considerably improved bone healing in the HPD-sheep. Our results indicate that fracture healing requires central regulation and that thyroxine T4 and 17β-estradiol contribute to the complex pathomechanisms of delayed metaphyseal bone healing in HPD-sheep.
Sheep model for osteoporosis: sustainability and biomechanical relevance of low turnover osteoporosis induced by hypothalamic-pituitary disconnection.
Oheim Ralf,Beil Frank Timo,Köhne Till,Wehner Tim,Barvencik Florian,Ignatius Anita,Amling Michael,Clarke Iain J,Pogoda Pia
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
Hypothalamo-pituitary disconnection (HPD) leads to low bone turnover and osteoporosis in sheep. To determine the sustainability of bone loss and its biomechanical relevance, we studied HPD-sheep 24 months after surgery (HPD + OVX-24) in comparison to untreated control (Control), ovariectomized sheep (OVX), and sheep 12 months after HPD (HPD + OVX-12). We performed histomorphometric, HR-pQCT, and qBEI analyses, as well as biomechanical testing of all ewes studied. Twenty-four months after HPD, histomorphometric analyses of the iliac crest showed a significant reduction of BV/TV by 60% in comparison to Control. Cortical thickness of the femora measured by HR-pQCT did not change between 12 and 24 months after HPD but remained decreased by 30%. These structural changes were caused by a persisting depression of osteoblast and osteoclast cellular activity. Biomechanical testing of the femora showed a significant reduction of bending strength, whereas calcium content and distribution was found to be unchanged. In conclusion, HPD surgery leads to a persisting low turnover status with negative turnover balance in sheep followed by dramatic cortical and trabecular bone loss with consequent biomechanical impairment.
Serum leptin is correlated to high turnover in osteoporosis.
Hipmair Gunter,Böhler Nikolaus,Maschek Wilma,Soriguer Federico,Rojo-Martínez Gemma,Schimetta Wolfgang,Pichler Robert
Neuro endocrinology letters
OBJECTIVE:Clinical data have suggested that obesity protects against osteoporosis. Leptin, mainly secreted by white adipose tissue, might be involved by mediating an effect on bone metabolism. This study was conducted to investigate a possible relationship of leptin and bone turn-over in postmenopausal women with osteoporosis. METHODS:We measured bone mineral density (BMD), serum leptin levels and markers of bone metabolism, including osteocalcin and cross-laps in 44 patients with osteoporosis. The main group consisted of 32 postmenopausal women. RESULTS:Mean serum leptin was 13.1 microg/L and showed no statistically significant difference to the levels measured in a collective of normal persons adjusted for age and BMI. When related to serum cross-laps as markers of bone resorption, a positive correlation (p<0.05) was observed, whereas no correlation with osteocalcin could be seen. CONCLUSIONS:A dual control of bone formation by leptin is assumed: This involves local mechanisms acting on osteoblasts and a central inhibitory effect on bone metabolism via a hypothalamic relay. Our data indicate that the net effect of circulating leptin may cause bone loss and is significantly related to high-turnover serum bone markers, at least in postmenopausal women with osteoporosis.
A study of cognitive functions in female elderly patients with osteoporosis: a multi-center cross-sectional study.
Peng Wenfang,Li Zezhi,Guan Yangtai,Wang Dan,Huang Shan
Aging & mental health
OBJECTIVES:To investigate changes of cognitive performances in female elderly patients with osteoporosis and to determine whether any impairments can be attributed to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS:This cross-sectional study included 277 postmenopausal women, who were divided into an osteoporosis patients group (n = 170) and an age, gender and educational history matching control group (n = 107). All the subjects completed a set of neuropsychological tests for the elderly for cognitive assessment, which included measures of executive function, episodic memory, attention and processing speed, semantic memory, and visuospatial construction. Blood biomarkers for osteoporosis, as well as diurnal rhythms of cortisol levels were used as cognitive performance correlation parameters in linear multivariate regression analyses. RESULTS:Individuals with osteoporosis had poorer cognitive scores (P < 0.001). When dividing the osteoporosis patients according to their Mini-Mental State Examination scores into mild cognitive impairment (MCI) and normal cognitive (NC) performance groups, Auditory Verbal Learning trial 1-5 scores were lower (P = 0.006) and Trail Making Test-A scores were higher (P = 0.05) in the MCI compared to the NC group. Further comparison of the MCI and NC groups revealed that declarative memory was inversely associated with cortisol levels (P < 0.001), but this association became marginal when 25-hydroxy vitamin D was included in the linear multivariate regression analyses (P = 0.06). CONCLUSIONS:Patients with osteoporosis are prone to cognitive impairments especially declarative memory deficits. The cognitive impairment may be the result of HPA axis dysregulation but 25-hydroxy vitamin D serum concentrations might be compensatory or even a potent contributing factor.
Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.
Suarez-Bregua Paula,Torres-Nuñez Eva,Saxena Ankur,Guerreiro Pedro,Braasch Ingo,Prober David A,Moran Paloma,Cerda-Reverter Jose Miguel,Du Shao Jun,Adrio Fatima,Power Deborah M,Canario Adelino V M,Postlethwait John H,Bronner Marianne E,Cañestro Cristian,Rotllant Josep
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Regulation of bone development, growth, and remodeling traditionally has been thought to depend on endocrine and autocrine/paracrine modulators. Recently, however, brain-derived signals have emerged as key regulators of bone metabolism, although their mechanisms of action have been poorly understood. We reveal the existence of an ancient parathyroid hormone (Pth)4 in zebrafish that was secondarily lost in the eutherian mammals' lineage, including humans, and that is specifically expressed in neurons of the hypothalamus and appears to be a central neural regulator of bone development and mineral homeostasis. Transgenic fish lines enabled mapping of axonal projections leading from the hypothalamus to the brainstem and spinal cord. Targeted laser ablation demonstrated an essential role for of pth4-expressing neurons in larval bone mineralization. Moreover, we show that Runx2 is a direct regulator of pth4 expression and that Pth4 can activate cAMP signaling mediated by Pth receptors. Finally, gain-of-function experiments show that Pth4 can alter calcium/phosphorus levels and affect expression of genes involved in phosphate homeostasis. Based on our discovery and characterization of Pth4, we propose a model for evolution of bone homeostasis in the context of the vertebrate transition from an aquatic to a terrestrial lifestyle.-Suarez-Bregua, P., Torres-Nuñez, E., Saxena, A., Guerreiro, P., Braasch, I., Prober, D. A., Moran, P., Cerda-Reverter, J. M., Du, S. J., Adrio, F., Power, D. M., Canario, A. V. M., Postlethwait, J. H., Bronner, M E., Cañestro, C., Rotllant, J. Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.
Nocturnal oxytocin secretion is lower in amenorrheic athletes than nonathletes and associated with bone microarchitecture and finite element analysis parameters.
Lawson Elizabeth A,Ackerman Kathryn E,Estella Nara Mendes,Guereca Gabriela,Pierce Lisa,Sluss Patrick M,Bouxsein Mary L,Klibanski Anne,Misra Madhusmita
European journal of endocrinology
OBJECTIVE:Preclinical data indicate that oxytocin, a hormone produced in the hypothalamus and secreted into the peripheral circulation, is anabolic to bone. Oxytocin knockout mice have severe osteoporosis, and administration of oxytocin improves bone microarchitecture in these mice. Data suggest that exercise may modify oxytocin secretion, but this has not been studied in athletes in relation to bone. We therefore investigated oxytocin secretion and its association with bone microarchitecture and strength in young female athletes. DESIGN:Cross-sectional study of 45 females, 14-21 years (15 amenorrheic athletes (AA), 15 eumenorrheic athletes (EA), and 15 nonathletes (NA)), of comparable bone age and BMI. METHODS:We used high-resolution peripheral quantitative CT to assess bone microarchitecture and finite element analysis to estimate bone strength at the weight-bearing distal tibia and non-weight-bearing ultradistal radius. Serum samples were obtained every 60 min, 2300-0700 h, and pooled for an integrated measure of nocturnal oxytocin secretion. Midnight and 0700 h samples were used to assess diurnal variation of oxytocin. RESULTS:Nocturnal oxytocin levels were lower in AA and EA than in NA. After controlling for estradiol, the difference in nocturnal oxytocin between AA and NA remained significant. Midnight and 0700 h oxytocin levels did not differ between groups. At the tibia and radius, AA had impaired microarchitecture compared with NA. In AA, nocturnal oxytocin correlated strongly with trabecular and cortical microarchitecture, particularly at the non-weight-bearing radius. In regression models that include known predictors of microarchitecture in AA, oxytocin accounted for a substantial portion of the variability in microarchitectural and strength parameters. CONCLUSIONS:Nocturnal oxytocin secretion is low in AA compared with NA and associated with site-dependent microarchitectural parameters. Oxytocin may contribute to hypoestrogenemic bone loss in AA.
Associations between hypothalamic-pituitary-adrenal axis function and peak bone mass at 20years of age in a birth cohort.
Zhu Kun,Henley David,Pennell Craig,Herbison Carly E,Mountain Jenny,Lye Stephen,Walsh John P
In older adults, high-normal circulating cortisol levels are associated with lower bone mass, but relationships between hypothalamic-pituitary-adrenal axis function and peak bone mass in young adults have not been examined. We studied 411 male and 390 female participants in the Western Australia Pregnancy Cohort (Raine) Study. At 18years of age, participants underwent a Trier Social Stress Test (TSST) with measurement of plasma and salivary cortisol at baseline and at multiple time points after stress. Cortisol responses were classified as anticipatory responder (significant fall in cortisol during the test), reactive responder (significant increase) or non-responder. At 20years, total body bone mineral content (BMC) and density (BMD) were measured by DXA. In males, after adjustment for weight, height (for BMC and bone area only), alcohol and smoking, there was a significant inverse relationship between both plasma and salivary cortisol measured at baseline in the TSST and each of BMC and BMD, such that each additional 10% of salivary cortisol was associated with reductions of 6.9g (95% CI -11.7, -2.2) in BMC, and 1.8mg/cm(2) (95% CI -3.3, -0.4) in BMD. Males classified as anticipatory responders in the TSST had 3.2% lower BMC (adjusted mean±SE: 3131±28 vs. 3233±18g, P=0.006) and 2.5% lower BMD (1108±9 vs. 1136±6mg/cm(2), P=0.022) than reactive responders. In females, there were no significant relationships between baseline cortisol or TSST responses and BMC or BMD in covariate-adjusted analyses. We conclude that in young males (but not females), higher circulating cortisol at the baseline of the stress test and an anticipatory responder pattern on the TSST are associated with lower total body bone mass.
Bone: Another potential target to treat, prevent and predict diabetes.
Liu Dong-Mei,Mosialou Ioanna,Liu Jian-Min
Diabetes, obesity & metabolism
Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggests that bone-derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and to highlight potential new means of therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism is osteocalcin (OCN), which functions in its active form, that is, undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favouring glucose and fatty acid uptake and utilization. A second bone-derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of the receptor activator of nuclear factor κ-B ligand, neuropeptide Y, and other known and unidentified bone-derived factors that function in glucose homeostasis. We summarize recent advances and the rationale for treating, preventing and predicting diabetes by skeleton intervention.
Different effects on bone strength and cell differentiation in pre pubertal caloric restriction versus hypothalamic suppression.
Joshi R N,Safadi F F,Barbe M F,Del Carpio-Cano Fe,Popoff S N,Yingling V R
Hypothalamic amenorrhea and energy restriction during puberty affect peak bone mass accrual. One hypothesis suggests energy restriction alters hypothalamic function resulting in suppressed estradiol levels leading to bone loss. However, both positive and negative results have been reported regarding energy restriction and bone strength. Therefore, the purpose of this study was to investigate energy restriction and hypothalamic suppression during pubertal onset on bone mechanical strength and the osteogenic capacity of bone marrow-derived cells in two models: female rats treated with gonadotropin releasing hormone antagonists (GnRH-a) or 30% energy restriction. At 23 days of age, female Sprague Dawley rats were assigned to three groups: control group (C, n=10), GnRH-a group (n=10), and Energy Restriction (ER, n=12) group. GnRH-a animals received daily injections for 27 days. The animals in the ER group received 70% of the control animals' intake. After sacrifice (50 days of age), body weight, uterine and muscle weights were measured. Bone marrow-derived stromal cells were cultured and assayed for proliferation and differentiation into osteoblasts. Outcome measures included bone strength, bone histomorphometry and architecture, serum IGF-1 and osteocalcin. GnRH-a suppressed uterine weight, decreased osteoblast proliferation, bone strength, trabecular bone volume and architecture compared to control. Elevated serum IGF-1 and osteocalcin levels and body weight were found. The ER model had an increase in osteoblast proliferation compared to the GnRH-a group, similar bone strength relative to body weight and increased trabecular bone volume in the lumbar spine compared to control. The ER animals were smaller but had developed bone strength sufficient for their size. In contrast, suppressed estradiol via hypothalamic suppression resulted in bone strength deficits and trabecular bone volume loss. In summary, our results support the hypothesis that during periods of nutritional stress the increased vertebral bone volume may be an adaptive mechanism to store mineral which differs from suppressed estradiol resulting from hypothalamic suppression.
Relationships Between Thyroid Hormones, Insulin-Like Growth Factor-1 and Antioxidant Levels in Hypothalamic Amenorrhea and Impact on Bone Metabolism.
Mancini Antonio,Vergani Edoardo,Bruno Carmine,Barini Angelina,Silvestrini Andrea,Meucci Elisabetta,Messana Calogero,Romualdi Daniela,Apa Rosanna,Lanzone Antonio
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Reduced bone mineral density (BMD) in Functional Hypothalamic Amenorrhea (FHA) is mainly related to hypoestrogenism, but other hormonal derangement (reduced conversion of T4-T3 and GH resistance) can play a role. These hormones are involved in antioxidant systems regulation. We evaluated the impact of hormonal alterations, with special focus on low T3 and IGF-1 levels, on antioxidant systems as a link with osteoporosis in FHA. Forty-three FHA patients, 15-34 years, with BMI range 17.3-23.4 kg/m, were divided in 2 groups according to fT3 levels; group A (n=22), low fT3 (<2.4 pg/ml) and group B (n=21), normal fT3 (≥ 2.4 pg/ml). We evaluated hormonal parameters (fT3, fT4, TSH, IGF-1, FSH, LH, estradiol, DHEAS, testosterone, cortisol), bone metabolism (calcium, phosphorus, 25-OH Vitamin D, PTH, β-crosslaps, bone alkaline phosphatase) and total antioxidant capacity (TAC), expressed as LAG (latency time in radical species appearance using spectrophotometric method). BMD was assessed by DEXA. Group A patients exhibited significantly lower levels of IGF-1 (159.76±14.79 vs. 220.05±15.25 ng/ml) and osteocalcin (17.51±1.14 vs. 21.49±1.56 ng/ml); LAG values were significantly higher in A (66.33±1.74 s) vs. B (54.62±1.74 s). A significant direct correlation was found between both IGF-1 and fT3 with osteocalcin (r²=0.22, p=0.0049 and r²=0.34, p=0.0001, respectively). No difference in LAG between groups according to IGF-1 were found. These data show a correlation between altered bone turnover and low fT3, which is highly prevalent in FHA. Low fT3 levels may contribute to reduced BMD. Oxidative stress could be the link underlying different bone turnover pattern and endocrine dysfunction in FHA.
Hypothalamic control of bone metabolism.
Sharan Kunal,Yadav Vijay K
Best practice & research. Clinical endocrinology & metabolism
Bones are structures in vertebrates that provide support to organs, protect soft organs, and give them shape and defined features, functions that are essential for their survival. To perform these functions, bones are constantly renewed throughout life. The process through which bones are renewed is known as bone remodeling, an energy demanding process sensitive to changes in energy homeostasis of the organism. A close interplay takes place between the diversity of nutritional cues and metabolic signals with different elements of the hypothalamic circuits to co-ordinate energy metabolism with the regulation of bone mass. In this review, we focus on how mouse and human genetics have elucidated the roles of hormonal signals and neural circuits that originate in, or impinge on, the hypothalamus in the regulation of bone mass. This will help to understand the mechanisms whereby regulation of bone is gated and dynamically regulated by the hypothalamus.
The impact of peripheral serotonin on leptin-brain serotonin axis, bone metabolism and strength in growing rats with experimental chronic kidney disease.
Pawlak Dariusz,Domaniewski Tomasz,Znorko Beata,Oksztulska-Kolanek Ewa,Lipowicz Paweł,Doroszko Michał,Karbowska Malgorzata,Pawlak Krystyna
Chronic kidney disease (CKD) results in decreased bone strength. Serotonin (5-HT) is one of the critical regulators of bone health, fulfilling distinct functions depending on its synthesis site: brain-derived serotonin (BDS) favors osteoblast proliferation, whereas gut-derived serotonin (GDS) inhibits it. We assessed the role of BDS and peripheral leptin in the regulation of bone metabolism and strength in young rats with 5/6 nephrectomy. BDS synthesis was accelerated during CKD progression. Decreased peripheral leptin in CKD rats was inversely related to BDS content in the hypothalamus, brainstem and frontal cortex. Serotonin in these brain regions affected bone strength and metabolism in the studied animals. The direct effect of circulating leptin on bone was not shown in uremia. At the molecular level, there was an inverse association between elevated GDS and the expression of cAMP responsive element-binding protein (Creb) gene in bone of CKD animals. In contrast, increased expression of activating transcription factor 4 (Atf4) was shown, which was associated with GDS-dependent transcription factor 1 (Foxo1), clock gene - Cry-1, cell cycle genes: c-Myc, cyclins, and osteoblast differentiation genes. These results identified a previously unknown molecular pathway, by which elevated GDS can shift in Foxo1 target genes from Creb to Atf4-dependent response, disrupting the leptin-BDS - dependent gene pathway in the bone of uremic rats. Thus, in the condition of CKD the effect of BDS and GDS on bone metabolism and strength can't be distinguished.
PYY is a negative regulator of bone mass and strength.
Leitch Victoria D,Brassill Mary Jane,Rahman Sofia,Butterfield Natalie C,Ma Pattara,Logan John G,Boyde Alan,Evans Holly,Croucher Peter I,Batterham Rachel L,Williams Graham R,Bassett J H Duncan
OBJECTIVE:Bone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass. METHODS:The skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing. RESULTS:Bones from juvenile and Pyy KO mice were longer (P < 0.001), with decreased bone mineral content (P < 0.001). Whereas, bones from adult Pyy KO mice had increased bone mineral content (P < 0.05) with increased mineralisation of both cortical (P < 0.001) and trabecular (P < 0.001) compartments. Long bones from adult Pyy KO mice were stronger (maximum load P < 0.001), with increased stiffness (P < 0.01) and toughness (P < 0.05) compared to wild-type (WT) control mice despite increased cortical vascularity and porosity (P < 0.001). The increased bone mass and strength in Pyy KO mice resulted from increases in trabecular (P < 0.01) and cortical bone formation (P < 0.05). CONCLUSIONS:These findings demonstrate that PYY acts as a negative regulator of osteoblastic bone formation, implicating increased PYY levels in the pathogenesis of bone loss during anorexia or following bariatric surgery.
ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure.
Idelevich Anna,Sato Kazusa,Nagano Kenichi,Rowe Glenn,Gori Francesca,Baron Roland
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Energy metabolism and bone homeostasis share several regulatory pathways. The AP1 transcription factor ΔFosB and leptin both regulate energy metabolism and bone, yet whether their pathways intersect is not known. Transgenic mice overexpressing ΔFosB under the control of the Enolase 2 (ENO2) promoter exhibit high bone mass, high energy expenditure, low fat mass, and low circulating leptin levels. Because leptin is a regulator of bone and ΔFosB acts on leptin-responsive ventral hypothalamic (VHT) neurons to induce bone anabolism, we hypothesized that regulation of leptin may contribute to the central actions of ΔFosB in the VHT. To address this question, we used adeno-associated virus (AAV) expression of ΔFosB in the VHT of leptin-deficient ob/ob mice and genetic crossing of ENO2-ΔFosB with ob/ob mice. In both models, leptin deficiency prevented ΔFosB-triggered reduction in body weight, increase in energy expenditure, increase in glucose utilization, and reduction in pancreatic islet size. In contrast, leptin deficiency failed to prevent ΔFosB-triggered increase in bone mass. Unlike leptin deficiency, galanin deficiency blocked both the metabolic and the bone ΔFosB-induced effects. Overall, our data demonstrate that, while the catabolic energy metabolism effects of ΔFosB require intact leptin and galanin signaling, the bone mass-accruing effects of ΔFosB require galanin but are independent of leptin. © 2019 American Society for Bone and Mineral Research.
Brain neural effects of the 'tonifying kidney and benefiting marrow' method in the treatment of osteoporosis.
Xu Yunxiang,Liu Xueqin,Li Haolan,Liu Hongyuan,Pan Zhanxia,Chen Guizhen
Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan
In Traditional Chinese Medicine (TCM), the 'tonifying kidney and benefiting marrow' (TKBM) method is based on the theory that kidney controls bones, while marrow moistens bones. There have been aboundant theoretical studies on kidney controlling bones since Huangdi's Internal Classics. However, there are too few ones about the marrow moistening the bones. Researchers generally use the tonifying kidney method instead of the TKBM method, which causes lack of a unified standard and theoretical basis in evaluating the TKBM method. Herein, we first proposed the hypothesis that deficiency of marrow sea causes osteoporosis. Next, we prove the scientific validity of this hypothesis from the side of the TCM theory on the relationship among kidney, bone and marrow sea physiologically and pathologically. Based on this, we find that the TCM theory provides theoretical basis for deficiency of marrow sea causing osteoporosis. On the other side, Western Medicine theory holds that (a) physiologically, the brain regulates the bone mass via three pathways: the neuro-osteogenic network, neuro-endocrine-bone network, and neuropeptide-bone network; (b) pathologically, brain impacts bone mass via three major passways including the regulation of the sympathetic nervous system, secreting hormones that directly act on bone cells and regulating the synthesis and secretion of hormones in the intermediary organs, and neuropeptides such as neuropeptide Y (NPY), substance P (SP), and calcitonin gene-related peptide (CGRP). Evidences involving estrogen deficiency, sympatheticotonia, or neuropeptides imbalance prove that brain-bone mass regulation plays an important role in the pathogenesis of osteoporosis. Finally, we find that kidney invigoration method can change the concentrations of central neurotransmitters of norepinephrine and glutamate to regulate neuro-osteogenic network, and promote the recovery of ovarian function and have an estrogen-like effect by regulating the hypothalamus-pituitary-ovarian axis, which thus influences bone metabolism without clinically significant estrogen-like side effects, and regulate NPY, CGRP and SP involved in the bone metabolism. These further support our hypothesis by revealing the brain neural mechanism of the TCM kidney invigoration method for preventing and treating osteoporosis. In the future, neuroimaging techniques may be useful in exploring its neural effects and also aid in developing new strategies for treating osteoporosis.
Brain to bone: What is the contribution of the brain to skeletal homeostasis?
Idelevich Anna,Baron Roland
The brain, which governs most, if not all, physiological functions in the body, from the complexities of cognition, learning and memory, to the regulation of basal body temperature, heart rate and breathing, has long been known to affect skeletal health. In particular, the hypothalamus - located at the base of the brain in close proximity to the medial eminence, where the blood-brain-barrier is not as tight as in other regions of the brain but rather "leaky", due to fenestrated capillaries - is exposed to a variety of circulating body cues, such as nutrients (glucose, fatty acids, amino acids), and hormones (insulin, glucagon, leptin, adiponectin) [1-3].Information collected from the body via these peripheral cues is integrated by hypothalamic sensing neurons and glial cells [4-7], which express receptors for these nutrients and hormones, transforming these cues into physiological outputs. Interestingly, many of the same molecules, including leptin, adiponectin and insulin, regulate both energy and skeletal homeostasis. Moreover, they act on a common set of hypothalamic nuclei and their residing neurons, activating endocrine and neuronal systems, which ultimately fine-tune the body to new physiological states. This review will focus exclusively on the brain-to-bone pathway, highlighting the most important anatomical sites within the brain, which are known to affect bone, but not covering the input pathways and molecules informing the brain of the energy and bone metabolic status, covered elsewhere [8-10]. The discussion in each section will present side by side the metabolic and bone-related functions of hypothalamic nuclei, in an attempt to answer some of the long-standing questions of whether energy is affected by bone remodeling and homeostasis and vice versa.