Repair of osteoporotic bone defects (OBD) remains a clinical challenge due to dysregulated bone homeostasis, characterized by impaired osteogenesis and excessive osteoclast activity. While drug-loaded 3D-printed scaffolds hold great potential in the restoration of bone homeostasis for enhanced OBD repair, achieving the controlled release and targeted delivery of drugs in a 3D-printed scaffold is still unmet. Herein, we developed an electrostatic encapsulation strategy to motivate 3D-printed polyelectrolyte scaffolds (APS@P) with bone-targeting liposome formulation of salvianolic acid B (SAB-BTL). Benefiting from this strategy, SAB, an unstable and untargetable plant-derived osteogenic compound, was effectively encapsulated in APS@P, demonstrating stable and precise delivery with improved therapeutic efficacy. Owing to SAB-mediated bone homeostasis, APS@P significantly promoted angiogenesis and new bone formation while suppressing bone resorption, resulting in a significant 146 % increase in bone mass and improved microstructure compared to the OBD group. It was confirmed that the encapsulation of SAB into APS@P could promote the osteogenic differentiation of MSCs by stimulating Tph2/Wnt/β-catenin signaling axis, coupled with the stimulation of type H angiogenesis and the suppression of RANKL-mediate bone resorption, thereby enhance OBD repair. This study provides a universal platform for enhancing the bioactivity of tissue-engineered scaffolds, offering an effective solution for the efficient regeneration of osteoporotic bone.

In the past two decades, the high demand of and significance of poultry meat have promoted the development of the goose industry. Despite the continuous expansion of the goose breeding scale and the generation of large economic benefits by the goose industry, low reproductive efficiency remains a barrier to limit vigorous development of the goose industry. Poor reproductive efficiency can be attributed to breeding seasonality, strong broody behavior, and poor semen quality. Based on the reproductive endocrine regulation mechanism of geese, an overview of past studies that have developed various methods to achieve a significant improvement in goose reproductive performance including physical facilities for artificial illumination control and dietary nutrition manipulation to improve breeder reproductivity, and artificial incubation equipment and technology for better hatchability. The most recent advances utilize immunoneutralization to regulate critical hormones involved in goose reproduction. This review provides new information for industry and academic studies of goose breeding.

The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair. Although the role of peripheral nerves and signals in regulating bone homeostasis has been extensively investigated, the intimate relationship between the central nervous system and bone remains less understood, yet it has emerged as a hot topic in the bone field. In this review, we discussed clinical observations and animal studies that elucidate the connection between the nervous system and bone metabolism, either intact or after injury. First, we explored mechanistic studies linking specific brain nuclei with bone homeostasis, including the ventromedial hypothalamus, arcuate nucleus, paraventricular hypothalamic nucleus, amygdala, and locus coeruleus. We then focused on the characteristics of bone innervation and nerve subtypes, such as sensory, sympathetic, and parasympathetic nerves. Moreover, we summarized the molecular features and regulatory functions of these nerves. Finally, we included available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration. Therefore, considering the nervous system within the context of neuromusculoskeletal interactions can deepen our understanding of skeletal homeostasis and repair process, ultimately benefiting future clinical translation.

Recent literature has increasingly demonstrated the significant function of autonomic nerves in regulating physiological and pathological changes associated with the skeletal system. Extensive studies have been conducted to understand the contribution of the autonomic nervous system (ANS) to skeletal metabolic homeostasis and resistance to aseptic inflammation, specifically from the viewpoint of skeletal neurobiology. There have been plenty of studies on how the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), the two main branches of the ANS, regulate bone remodeling, which is the process of bone formation and resorption. The following studies have revealed critical neurological pathways that induce significant alterations in bone cell biology and uncover the intricate linkages between the ANS and the skeletal system. Furthermore, inspired by the connection between the ANS and bone remodeling, neuromodulation has been utilized as a therapeutic method for patients with orthopedic diseases: by directly influencing the ANS, it is possible to alter the excitability of nerve fibers and the release of neurotransmitters, which can lead to anti-inflammatory and analgesic effects, thereby directly or indirectly impacting bone formation and bone resorption. Our work aims to review the most recent findings on the impact of the ANS on bone remodeling, enhance the current understanding of the interaction between nerves and bones, and explore potential neuromodulation methods that could be used to treat orthopedic conditions, thereby drawing attention to the significant role of the ANS in the skeletal system.

More than 1 million people in the United States meet the criteria for cocaine use disorder (CUD), and over 19,000 people died from cocaine-related overdoses in 2020, but there are currently no FDA-approved medications for the treatment of CUD. Bupropion is an antidepressant currently prescribed to treat depression and nicotine addiction that acts by inhibiting norepinephrine and dopamine transporters.

In this study, we tested the effect of several doses of systemic bupropion on cocaine self-administration in male and female Wistar rats. In our first experiment, rats self-administered cocaine solution intravenously and were pretreated with systemic bupropion before self-administration sessions. In our second experiment, rats were pre-treated with bupropion before completing tests of locomotor activity and anxiety-like behavior.

We found that high doses of systemically administered bupropion (60 mg/kg) attenuated cocaine self-administration in male and female rats during extended-access (6 h) sessions. We also found that the highest dose (60 mg/kg) of systemic bupropion was more efficacious in females relative to males during the first hour of operant sessions. Systemic bupropion did not alter locomotor activity, inactive lever presses, or food intake. The Estrous cycle did not influence cocaine intake with or without bupropion.

Our finding that bupropion attenuates cocaine self-administration suggests that bupropion may have promise for reducing cocaine use in humans.

The present study was designed to explore whether the depletion of serotonin (5-HT) in the central nervous system (CNS5-HT) leads to systolic and diastolic dysfunction and whether this dysfunction is exacerbated by sex, age and spinal cord injury. Echocardiographic assessment of systolic and diastolic function was completed in young and old male and female tryptophan hydroxylase 2 knockout (TPH2-/-) and wild-type (TPH2+/+) mice with intact spinal cords, as well as in C2  spinal cord hemisected young TPH2-/- and TPH2+/+ mice. In addition, lumbar sympathetic nervous system activity was recorded in elderly male and female intact TPH2-/- and TPH2+/+ mice. Systolic and diastolic dysfunction was evident in young TPH2-/- mice, including a higher left ventricular mass (P < 0.001), left ventricular outflow parameters (e.g. peak velocity) and E/A (P < 0.001). Reductions in ejection fraction and fractional shortening were also evident (P < 0.001), although stroke volume and cardiac output were maintained. The assessed dysfunction was exacerbated by age and spinal cord injury, resulting in reductions in cardiac output (P ≤ 0.01). The dysfunction was accompanied by increases in sympathetic burst height (P = 0.038) and incidence (P = 0.001). Reductions in CNS5-HT are coupled to systolic and diastolic dysfunction, which is exacerbated by age and spinal cord injury. This dysfunction is coupled to increases in sympathetic nervous system activity in elderly mice. Our findings are an initial step toward determining whether reductions in CNS5-HT are a unifying mechanism that links central sleep apnoea, sympathoexcitation and heart failure in intact and spinal cord injured individuals. KEY POINTS: Reductions in central nervous system serotonin (CNS5-HT) may contribute to systolic and diastolic dysfunction. This dysfunction may be linked to increases in sympathetic nervous system activity and exacerbated by sex, age and spinal cord injury. Echocardiographic assessment of systolic and diastolic function was completed in young and old male and female intact TPH2+/+ and TPH2-/- mice, as well as in C2 spinal cord hemisected young mice. Lumbar sympathetic nervous system activity was also recorded in elderly male and female intact TPH2+/+ and TPH2-/- mice. Systolic and diastolic dysfunction was evident in young TPH2-/- mice. This dysfunction was exacerbated by age and spinal cord injury. The cardiac dysfunction was accompanied by increases in lumbar sympathetic nervous system activity. Our findings are an initial step toward determining whether reductions in CNS5-HT is a unifying mechanism that links central sleep apnoea, sympathoexcitation and heart failure in intact and spinal cord injured individuals.

Semaphorin 3A (Sema3A) is a signaling protein that has attracted increasing attention in recent years for its important role in regulating bone metabolism. In this review, we searched different databases with various combinations of keywords to analyze the effects of Sema3A on osteoporosis. Sema3A promotes bone formation and inhibits bone resorption by directly affecting the osteoblast and osteoclast or indirectly targeting the nervous system. The sympathetic nervous system may be the main link between the central nervous system and bone metabolism for Sema3A. In the peripheral nervous system, Sema3A may improve bone quality via sensory nervous innervation. In addition, estrogen is found to regulate Sema3A levels to improve bone homeostasis. Lots of Sema3A agonists have been documented to exhibit anti-osteoporotic potential in preclinical investigations. Therefore, Sema3A can be considered a novel therapeutic target for preserving bone mass, highlighting an alternative strategy for the development of anti-osteoporosis drugs.

Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HTDRN➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.

Knowledge of the complex interplay between gut microbiota and human health is gradually increasing as it has just recently been a field of such great interest.

Recent studies have reported that communities of microorganisms inhabiting the gut influence the immune system through cellular responses and shape many physiological and pathophysiological aspects of the body, including muscle and bone metabolism (formation and resorption). Specifically, the gut microbiota affects skeletal homeostasis through changes in host metabolism, the immune system, hormone secretion, and the gut-brain axis. The major role on gut-bone axis is due to short-chain fatty acids (SCFAs). They have the ability to influence regulatory T-cell (Tregs) development and activate bone metabolism through the action of Wnt10. SCFA production may be a mechanism by which the microbial community, by increasing the serum level of insulin-like growth factor 1 (IGF-1), leads to the growth and regulation of bone homeostasis. A specific SCFA, butyrate, diffuses into the bone marrow where it expands Tregs. The Tregs induce production of the Wnt ligand Wnt10b by CD8+ T cells, leading to activation of Wnt signaling and stimulation of bone formation. At the hormonal level, the effect of the gut microbiota on bone homeostasis is expressed through the biphasic action of serotonin. Some microbiota, such as spore-forming microbes, regulate the level of serotonin in the gut, serum, and feces. Another group of bacterial species (Lactococcus, Mucispirillum, Lactobacillus, and Bifidobacterium) can increase the level of peripheral/vascular leptin, which in turn manages bone homeostasis through the action of brain serotonin.

Leptin is a homeostatic regulatory element that signals the presence of adipocyte energy stores, reduces food intake, and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also controls food intake. Using neuronal tract tracing, pharmacologic and optogenetic approaches, and in vivo microdialysis, combined with behavioral end points, we tested the hypothesis that leptin controls food intake not only by activating hypothalamic leptin receptors (LepRs) but also through activation of LepRs expressed by serotonergic raphe neurons that send projections to the arcuate (ARC). We showed that microinjection of leptin directly into the dorsal raphe nucleus (DRN) reduced food intake in rats. This effect was mediated by LepR-expressing neurons in the DRN, because selective optogenetic activation of these neurons at either their DRN cell bodies or their ARC terminals reduced food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing LepRs that send projections to the ARC. Finally, by using in vivo microdialysis, we showed that leptin administration to the DRN increased 5-HT efflux into the ARC, and specific antagonism of the 5-HT2C receptors in the ARC diminished the leptin anorectic effect. Overall, this study identified a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, identifying a new level of interaction between leptin and serotonin to control food intake. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior and opens alternative routes for the treatment of eating disorders.

Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological function of the serotonin 2C receptor (5-HT2C receptor) make it a candidate of interest for the treatment of SUD. Recently, psychedelics, which broadly act at 5-HT2 receptors, have indicated potential for the treatment of SUD, implicating the 5-HT2C receptor. The modern psychedelic movement has rekindled interest in the 5-HT2C receptor, resulting in many new studies, especially structural analyses. This review explores the structural, molecular and cellular mechanisms governing 5-HT2C receptor function in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration.

Leptin, a hormone secreted by adipose tissue, plays a pivotal role in maintaining energy metabolism and bone quality. Dysregulation of leptin can lead to the development of various pathological conditions. For example, the concentration of leptin is increased in individuals with obesity, and this increased concentration is positively correlated with higher bone mass. In addition, mice lacking leptin or the leptin receptor exhibit substantial bone loss, further highlighting the pivotal role of leptin in regulating bone metabolism. However, the precise mechanism through which leptin affects bone remodeling remains unclear. The present study investigated the effect of leptin on osteoclastogenesis and osteoblastogenesis. Osteoblasts derived from MC3T3-E1 cells and osteoclasts derived from RAW 264.7 cells were used. The findings revealed that leptin did not substantially affect osteoclastogenesis or osteoblastogenesis. Furthermore, leptin did not affect cell viability during osteoclast differentiation. The expression of inflammatory mediators was increased in differentiating RAW 264.7 cells. However, the expression of critical bone resorptive genes, including Ctsk and tartrate-resistant acid phosphatase, was not elevated following leptin stimulation. By contrast, leptin did not alter the expression of key osteogenic genes in preosteoblasts in the early stage of differentiation. These data demonstrate that leptin can stimulate the expression of pro-inflammatory mediators in differentiating osteoclasts. These changes do not affect osteoblastogenesis or osteoclastogenesis. Leptin may downregulate bone resorption and enhance mineralization to increase bone mass.

The intrinsic correlation between depression and serotonin (5-HT) is a highly debated topic, with significant implications for the diagnosis, treatment, and advancement of drugs targeting neurological disorders. To address this important question, it is of utmost priority to understand the action mechanism of serotonin in depression through fluorescence imaging studies. However, the development of efficient molecular probes for serotonin is hindered by the lack of responsive sites with high selectivity for serotonin at the present time. Herein, we developed the first highly selective serotonin responsive site, 3-mercaptopropionate, utilizing thiol-ene click cascade nucleophilic reactions. The novel responsive site was then employed to construct the powerful molecular probe SJ-5-HT for imaging the serotonin level changes in the depression cells and brain tissues. Importantly, the imaging studies reveal that the level of serotonin in patients with depression may not be the primary factor, while the ability of neurons in patients with depression to release serotonin appears to be more critical. Additionally, this serotonin release capability correlates strongly with the levels of mTOR (intracellular mammalian target of rapamycin). These discoveries could offer valuable insights into the molecular mechanisms underpinning depression and furnish mTOR as a novel direction for the advancement of antidepressant therapies.

Peritendinous adhesion that forms after tendon injury substantially limits daily life. The pathology of adhesion involves inflammation and the associated proliferation. However, the current studies on this condition are lacking, previous studies reveal that cyclooxygenase-2 (COX2) gene inhibitors have anti-adhesion effects through reducing prostaglandin E2 (PGE2) and the proliferation of fibroblasts, are contrary to the failure in anti-adhesion through deletion of EP4 (prostaglandin E receptor 4) gene in fibroblasts in mice of another study. In this study, single-cell RNA sequencing analysis of human and mouse specimens are combined with eight types of conditional knockout mice and further reveal that deletion of COX2 in myeloid cells and deletion of EP4 gene in sensory nerves decrease adhesion and impair the biomechanical properties of repaired tendons. Furthermore, the COX2 inhibitor parecoxib reduces PGE2 but impairs the biomechanical properties of repaired tendons. Interestingly, PGE2 local treatment improves the biomechanical properties of the repaired tendons. These findings clarify the complex role of PGE2 in peritendinous adhesion formation (PAF) and tendon repair.

Leg disorders have become increasingly common in broilers, leading to lower meat quality and major economic losses. This study evaluated the effects of dietary supplementation with Clostridium butyricum (C. butyricum) and 25-hydroxyvitamin D3 (25-OH-D3) on bone development by comparing growth performance, tibial parameters, Ca and P contents of tibial ash, bone development-related indicators' level, and cecal short-chain fatty acids in Cobb broilers. All birds were divided into four treatment groups, which birds fed either a basal diet (Con), basal diet + 75 mg chlortetracycline/kg (Anti), basal diet + C. butyricum at 109 CFU/kg (Cb), basal diet + C. butyricum at 109 CFU/kg and 25-OH-D3 at 25 μg/kg (CbD), or basal diet + 25-OH-D3 at 25 μg/kg (CD). Our results suggest that the dietary supplementation in Cb, CbD, and CD significantly increased the body weight (BW) and average daily gain (ADG), and reduced the feed-to-weight ratio (F/G) at different stages of growth (P < 0.05). Dietary supplementation in Cb, CbD, and CD prolonged (P < 0.05) the behavioral responses latency-to-lie (LTL) time, reduced (P < 0.05) the levels of osteocalcin (BGP) and peptide tyrosine (PYY), and increased (P < 0.05) serotonin (5-HT) and dopamine (DA). Treatment with Cb increased (P < 0.05) the levels of acetic acid, isobutyric acid, butyric acid, and isovaleric acid compared with those in Con group. The cecal metagenome showed that Alistipes spp. were significantly more abundant in Cb, CbD, and CD groups (P < 0.05). A total of 12 metabolic pathways were significantly affected by supplementation, including the signaling pathways of glucagon, insulin, and PI3K-AKT; primary and secondary bile acid biosynthesis; and P-type Ca 2+ transporters (P < 0.05). Hence, the CbD supplementation modulates bone metabolism by regulating the mediators of gut-brain axis, which may inform strategies to prevent leg diseases and improve meat quality in broilers.

Serotonin reuptake inhibitor antidepressants such as fluoxetine are widely used to treat mood disorders. The mechanisms of action include an increase in extracellular level of serotonin, neurogenesis, and growth of vessels in the brain. We investigated whether fluoxetine could have broader peripheral regenerative properties. Following prolonged administration of fluoxetine in male mice, we showed that fluoxetine increases the number of muscle stem cells and muscle angiogenesis, associated with positive changes in skeletal muscle function. Fluoxetine also improved skeletal muscle regeneration after single and multiples injuries with an increased muscle stem cells pool and vessel density associated with reduced fibrotic lesions and inflammation. Mice devoid of peripheral serotonin treated with fluoxetine did not exhibit beneficial effects during muscle regeneration. Specifically, pharmacological, and genetic inactivation of the 5-HT1B subtype serotonin receptor also abolished the enhanced regenerative process induced by fluoxetine. We highlight here a regenerative property of serotonin on skeletal muscle.

Bone homeostasis in physiology depends on the balance between bone formation and resorption, and in pathology, this homeostasis is susceptible to disruption by different influences, especially under ageing condition. Gut microbiota has been recognized as a crucial factor in regulating host health. Numerous studies have demonstrated a significant association between gut microbiota and bone metabolism through host-microbiota crosstalk, and gut microbiota is even an important factor in the pathogenesis of bone metabolism-related diseases that cannot be ignored. This review explores the interplay between gut microbiota and bone metabolism, focusing on the roles of gut microbiota in bone ageing and aging-related bone diseases, including osteoporosis, fragility fracture repair, osteoarthritis, and spinal degeneration from different perspectives. The impact of gut microbiota on bone metabolism during aging through modification of endocrinology system, immune system and gut microbiota metabolites are summarized, facilitating a better grasp of the pathogenesis of aging-related bone metabolic diseases. This review offers innovative insights into targeting the gut microbiota for the treatment of bone ageing-related diseases as a clinical therapeutic strategy.

Postmenopausal osteoporosis (PMOP) is a major health problem affecting millions of women worldwide. PMOP patients are often accompanied by abnormal accumulation of bone marrow adipose tissue (BMAT). BMAT is a critical regulator of bone homeostasis, and an increasing BMAT volume is negatively associated with bone mass reduction or fracture. BMAT regulates bone metabolism via adipokines, cytokines and the immune system, but the specific mechanisms are largely unknown. This review emphasizes the impact of estrogen deficiency on bone homeostasis and BMAT expansion, and the mechanism by which BMAT regulates PMOP, providing a promising strategy for targeting BMAT in preventing and treating PMOP.

Increased β-adrenergic receptor activity has been hypothesized to cause bone loss in those with dementia. We investigated the effect of long-term β-blocker use on rate of bone loss in older adults with dementia. We used a linear mixed-effects model to estimate the relationship between long-term β-blocker use and rate of bone loss in participants from the Health Aging and Body Composition study. Records of 1198 participants were analyzed, 44.7% were men. Among the men, 25.2% had dementia and 20.2% were on β-blockers, while in the women, 22.5% had dementia and 16.6% received β-blockers. In the 135 men with dementia, 23 were taking β-blockers, while 15 of 149 women with dementia were using β-blockers. In men with dementia, β-blocker users had 0.00491 g/cm2 less bone mineral density (BMD) loss per year at the femoral neck (i.e., 0.63% less loss per year) than non-users (p < 0.05). No differences were detected in women with or without dementia and men without dementia. β-blockers may be protective by slowing down bone loss in older men with dementia.

Over the past decades, emerging evidence in the literature has demonstrated that the innervation of bone is a crucial modulator for skeletal physiology and pathophysiology. The nerve-bone axis sparked extensive preclinical and clinical investigations aimed at elucidating the contribution of nerve-bone crosstalks to skeleton metabolism, homeostasis, and injury repair through the perspective of skeletal neurobiology. To date, peripheral nerves have been widely reported to mediate bone growth and development and fracture healing via the secretion of neurotransmitters, neuropeptides, axon guidance factors, and neurotrophins. Relevant studies have further identified several critical neural pathways that stimulate profound alterations in bone cell biology, revealing a complex interplay between the skeleton and nerve systems. In addition, inspired by nerve-bone crosstalk, novel drug delivery systems and bioactive materials have been developed to emulate and facilitate the process of natural bone repair through neuromodulation, eventually boosting osteogenesis for ideal skeletal tissue regeneration. Overall, this work aims to review the novel research findings that contribute to deepening the current understanding of the nerve-bone axis, bringing forth some schemas that can be translated into the clinical scenario to highlight the critical roles of neuromodulation in the skeletal system.

In addition to its recognized role in providing structural support, bone plays a crucial role in maintaining the functionality and balance of various organs by secreting specific cytokines (also known as osteokines). This reciprocal influence extends to these organs modulating bone homeostasis and development, although this aspect has yet to be systematically reviewed. This review aims to elucidate this bidirectional crosstalk, with a particular focus on the role of osteokines. Additionally, it presents a unique compilation of evidence highlighting the critical function of extracellular vesicles (EVs) within bone-organ axes for the first time. Moreover, it explores the implications of this crosstalk for designing and implementing bone-on-chips and assembloids, underscoring the importance of comprehending these interactions for advancing physiologically relevant in vitro models. Consequently, this review establishes a robust theoretical foundation for preventing, diagnosing, and treating diseases related to the bone-organ axis from the perspective of cytokines, EVs, hormones, and metabolites.

The brain-bone axis has emerged as a captivating field of research, unveiling the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This comprehensive review delves into the current state of knowledge surrounding the brain-bone axis, exploring the complex mechanisms, key players, and potential clinical implications of this fascinating area of study. The review discusses the neural regulation of bone metabolism, highlighting the roles of the sympathetic nervous system, hypothalamic neuropeptides, and neurotransmitters in modulating bone remodeling. In addition, it examines the influence of bone-derived factors, such as osteocalcin and fibroblast growth factor 23, on brain function and behavior. The therapeutic potential of targeting the brain-bone axis in the context of skeletal and neurological disorders is also explored. By unraveling the complex interplay between the CNS and skeletal metabolism, this review aims to provide a comprehensive resource for researchers, clinicians, and students interested in the brain-bone axis and its implications for human health and disease.

Efficient regeneration of bone defects caused by disease or significant trauma is a major challenge in current medicine, which is particularly difficult yet significant under the emerging psychological stress in the modern society. Notably, the brain-bone axis has been proposed as a prominent new concept in recent years, among which autonomic nerves act as an essential and emerging skeletal pathophysiological factor related to psychological stress. Studies have established that sympathetic cues lead to impairment of bone homeostasis mainly through acting on mesenchymal stem cells (MSCs) and their derivatives with also affecting the hematopoietic stem cell (HSC)-lineage osteoclasts, and the autonomic neural regulation of stem cell lineages in bone is increasingly recognized to contribute to the bone degenerative disease, osteoporosis. This review summarizes the distribution characteristics of autonomic nerves in bone, introduces the regulatory effects and mechanisms of autonomic nerves on MSC and HSC lineages, and expounds the crucial role of autonomic neural regulation on bone physiology and pathology, which acts as a bridge between the brain and the bone. With the translational perspective, we further highlight the autonomic neural basis of psychological stress-induced bone loss and a series of pharmaceutical therapeutic strategies and implications toward bone regeneration. The summary of research progress in this field will add knowledge to the current landscape of inter-organ crosstalk and provide a medicinal basis for the achievement of clinical bone regeneration in the future.

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.

Serotonin (5-HT) precursors regulate bone remodeling. This study aims to investigate the correlation of plasma 5-HT precursors and metabolite with bone mineral density (BMD) and bone turnover markers in postmenopausal osteoporosis (PMOP) patients.

The age, body mass index (BMI), and years since menopause (YSM) were documented for 348 postmenopausal women in normal/osteopenia/osteoporosis (OP) groups, with lumbar spine and femoral neck BMD measured. Serum bone turnover markers (PINP/β-CTX) and plasma 5-HT, 5-HT precursors (Trp/5-HTP) and metabolite (5-HIAA) were measured by ELISA. OP patients were allocated to high/low expression groups following ROC analysis of 5-HT/Trp/5-HTP/5-HIAA. The relationship of plasma 5-HT/Trp/5-HTP/5-HIAA, BMD, and bone turnover markers with PMOP was analyzed using logistic regression analysis. The correlation of plasma 5-HT/Trp/5-HTP/5-HIAA with BMD and bone turnover markers was analyzed using Pearson's correlation analysis, followed by logistic regression analysis of the relationship between plasma 5-HT/Trp/5-HTP/5-HIAA and BMD, bone turnover markers and PMOP.

BMI, YSM, BMD and PINP, and β-CTX levels differed among groups. Levels of plasma 5-HT precursors/metabolite were increased in OP patients. Individuals with high 5-HT precursors/metabolite levels had low BMD and high PINP/β-CTX levels. The 5-HT precursors/metabolite negatively-correlated with BMD and positively-correlated with PINP/β-CTX. BMI, YSM, BMD, and PINP/β-CTX/Trp/5-HTP/5-HT related to PMOP and were independent risk factors for OP.

Plasma 5-HT precursors and metabolite negatively-correlate with BMD and positively-correlate with PINP/β-CTX in PMOP patients. Peripheral 5-HT precursors and metabolite level may be a new direction of treatment of PMOP and bone metabolism-related disorders.

The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve-bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.

T1D can be associated with metabolic disorders and several impaired pathways, including insulin signaling, and development of insulin resistance through the renin-angiotensin system (RAS). The main precursor of RAS is angiotensinogen (Agt) and this system is often linked to autophagy dysregulation. Dysregulated autophagy has been described in T1D and linked to impairments in both glucose metabolism, and leukotrienes (LTs) production. Here, we have investigated the role of RAS and LTs in both muscle and liver from T1D mice, and its effects on insulin and autophagy pathways. We have chemically induced T1D in 129sve and 129sve 5LO-/- mice (lacking LTs) with streptozotocin (STZ). To further inhibit ACE activity, mice were treated with captopril (Cap). In muscle of T1D mice, treatment with Cap increased the expression of RAS (angiotensinogen and angiotensin II receptor), insulin signaling, and autophagy markers, regardless of the genotype. In the liver of T1D mice, the treatment with Cap increased the expression of RAS and insulin signaling markers, mostly when LTs were absent. 5LO-/- T1D mice showed increased insulin sensitivity, and decreased NEFA, after the Cap treatment. Cap treatment impacted both insulin signaling and autophagy pathways at the mRNA levels in muscle and liver, indicating the potential role of ACE inhibition on insulin sensitivity and autophagy in T1D.

In recent decades, the global demographic landscape has undergone a discernible shift that has been characterised by a progressive increase in the proportion of elderly individuals, indicative of an enduring global inclination toward extended lifespans. The aging process, accompanied by physiological changes and dietary patterns, contributes to detrimental deviations in micronutrient consumption. This vulnerable aging population faces heightened risks, including dental caries, due to structural and functional modifications resulting from insufficient nutritional sustenance. Factors such as physiological changes, inadequate nutrition, and the prevalence of multiple chronic pathologies leading to polypharmacy contribute to the challenge of maintaining an optimal nutritional status. This scenario increases the likelihood of drug interactions, both between medications and with nutrients and the microbiome, triggering complications such as dental decay and other pathologies. Since the drug industry is evolving and new types of food, supplements, and nutrients are being designed, there is a need for further research on the mechanisms by which drugs interfere with certain nutrients that affect homeostasis, exemplified by the prevalence of caries in the mouths of older adults. Infectious diseases, among them dental caries, exert serious impacts on the health and overall quality of life of the elderly demographic. This comprehensive review endeavours to elucidate the intricate interplay among drugs, nutrients, the microbiome, and the oral cavity environment, with the overarching objective of mitigating the potential hazards posed to both the general health and dental well-being of older adults. By scrutinising and optimising these multifaceted interactions, this examination aims to proactively minimise the susceptibility of the elderly population to a spectrum of health-related issues and the consequences associated with dental decay.

The gut microbiome (GM) has become a crucial factor that can affect the progression of osteoporosis. A number of studies have demonstrated the impact of Traditional Chinese Medicine (TCM) on GM and bone metabolism. In this review, we summarize the potential mechanisms of the relationship between osteoporosis and GM disorder and introduce several natural Chinese medicines that exert anti-osteoporosis effects by modulating the GM. It is underlined that, through the provision of the microbial associated molecular pattern (MAMP), the GM causes inflammatory reactions and alterations in the Treg-Th17 balance and ultimately leads to changes in bone mass. Serotonin and many hormones, especially estrogen, may play a crucial role in the interaction of the GM with bone metabolism. Additionally, the GM may affect the absorption of specific nutrients in the intestine, particularly minerals like calcium, magnesium, and phosphorus. Several natural Chinese herbs, such as Sambucus Williamsii, Achyranthes bidentata Blume, Pleurotus ostreatus and Ganoderma lucidum mushrooms, Pueraria Lobata, and Agaricus blazei Murill have exhibited anti-osteoporosis effects through regulating the distribution and metabolism of the GM. These herbs may increase the abundance of Firmicutes, decrease the abundance of Bacteroides, promote the GM to produce more SCFAs, modulate the immune response caused by harmful bacteria, and increase the proportion of Treg-Th17 to indirectly affect bone metabolism. Moreover, gut-derived 5-HT is an important target for TCM to prevent osteoporosis via the gut-bone axis. Puerarin could prevent osteoporosis by improving intestinal mucosal integrity and decrease systemic inflammation caused by estrogen deficiency.

Osteoporosis is a systemic bone disease characterized by an imbalance in the relationship between osteoblasts, osteocytes, and osteoclasts. This imbalance in bone metabolism results in the destruction of the bone's microstructure and an increase in bone brittleness, thereby increasing the risk of fractures. Osteoporosis has complex causes, one of which is related to the dysregulation of 5-hydroxytryptamine, a neurotransmitter closely associated with bone tissue metabolism. Dysregulation of 5-HT directly or indirectly promotes the occurrence and development of osteoporosis. This paper aims to discuss the regulation of 5-HT by Traditional Chinese Medicine and its impact on bone metabolism, as well as the underlying mechanism of action. The results of this study demonstrate that Traditional Chinese Medicine has the ability to regulate 5-HT, thereby modulating bone metabolism and improving bone loss. These findings provide valuable insights for future osteoporosis treatment.

Recent studies have determined that the nervous system can sense and respond to signals from skeletal tissue, a process known as skeletal interoception, which is crucial for maintaining bone homeostasis. The hypothalamus, located in the central nervous system (CNS), plays a key role in processing interoceptive signals and regulating bone homeostasis through the autonomic nervous system, neuropeptide release, and neuroendocrine mechanisms. These mechanisms control the differentiation of mesenchymal stem cells into osteoblasts (OBs), the activation of osteoclasts (OCs), and the functional activities of bone cells. Sensory nerves extensively innervate skeletal tissues, facilitating the transmission of interoceptive signals to the CNS. This review provides a comprehensive overview of current research on the generation and coordination of skeletal interoceptive signals by the CNS to maintain bone homeostasis and their potential role in pathological conditions. The findings expand our understanding of intersystem communication in bone biology and may have implications for developing novel therapeutic strategies for bone diseases.

Tryptophan hydroxylase 2 (TPH2) is the key and rate-limited enzyme of serotonin (5-HT) synthesis in the brain. The C1473G mutation in the Tph2 gene results in a two-fold decrease in enzyme activity in the mouse brain. The lethal yellow (A^Y) mutation in the Raly-Agouti locus results in the overexpression of the Agouti gene in the brain and causes obesity and depressive-like behavior in mice. Herein, the possible influences of these mutations and their combination on body mass, behavior, brain 5-HT and melanocortin systems in mice of the B6-1473CC/aa. B6-1473CC/A^Ya, B6-1473GG/aa are investigated. B6-1473GG/A^Ya genotypes were studied. The 1473G and A^Y alleles increase the activity of TPH2 and the expression of the Agouti gene, respectively, but they do not alter 5-HT and 5-HIAA levels or the expression of the genes Tph2, Maoa, Slc6a4, Htr1a, Htr2a, Mc3r and Mc4r in the brain. The 1473G allele attenuates weight gain and depressive-like immobility in the forced swim test, while the A^Y allele increases body weight gain and depressive-like immobility. The combination of these alleles results in hind limb dystonia in the B6-1473GG/A^Ya mice. This is the first evidence for the interaction between the C1473G and A^Y mutations.

Leptin is a homeostatic regulatory element that signals the presence of energy stores -in the form of adipocytes-which ultimately reduces food intake and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also regulates food intake. Here we use a combination of pharmacological manipulations, optogenetics, retrograde tracing, and in situ hybridization, combined with behavioral endpoints to physiologically and anatomically identify a novel leptin-mediated pathway between 5-HT neurons in the dorsal raphe nucleus (DRN) and hypothalamic arcuate nucleus (ARC) that controls food intake. In this study, we show that microinjecting leptin directly into the DRN reduces food intake in male Sprague-Dawley rats. This effect is mediated by leptin-receptor expressing neurons in the DRN as selective optogenetic activation of these neurons at either their ARC terminals or DRN cell bodies also reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing leptin receptors that send projections to the ARC. Finally, by utilizing in vivo microdialysis and high-performance liquid chromatography, we show that leptin administration to the DRN increases 5-HT efflux into the ARC. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, utilizing 5-HT as a mechanism to control feeding behavior. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders.

Leptin and serotonin both play a vital role in the regulation of food intake, yet there is still uncertainty in how these two molecules interact to control appetite. The purpose of this study is to further understand the anatomical and functional connections between leptin receptor expressing neurons in the dorsal raphe nucleus, the main source of serotonin, and the arcuate nucleus of the hypothalamus, and how serotonin plays a role in this pathway to reduce food intake. Insight gained from this study will contribute to a more thorough understanding of the networks that regulate food intake, and open alternative avenues for the development of treatments for obesity and eating disorders.

Lactation is a physiological adaptation of the class Mammalia and is a product of over 200 million years of evolution. During lactation, the mammary gland orchestrates bone metabolism via serotonin signaling in order to provide sufficient calcium for the offspring in milk. The role of serotonin in bone remodeling was first discovered over two decades ago, and the interplay between serotonin, lactation, and bone metabolism has been explored in the years following. It is estimated that postpartum depression affects 10-15% of the population, and selective serotonin reuptake inhibitors (SSRI) are often used as the first-line treatment. Studies conducted in humans, nonhuman primates, sheep, and rodents have provided evidence that there are consequences on both parent and offspring when serotonin signaling is disrupted during the peripartal period; however, the long-term consequences of disruption of serotonin signaling via SSRIs during the peripartal period on the maternal and offspring skeleton are not fully known. This review will focus on the relationship between the mammary gland, serotonin, and bone remodeling during the peripartal period and the skeletal consequences of the dysregulation of the serotonergic system in both human and animal studies.

The bony skeleton, as a structural foundation for the human body, is essential in providing mechanical function and movement. The human skeleton is a highly specialized and dynamic organ that undergoes continuous remodeling as it adapts to the demands of its environment. Advances in research over the last decade have shone light on the various hormones that influence this process, modulating the metabolism and structural integrity of bone. More recently, novel and non-traditional functions of hypothalamic, pituitary, and adipose hormones and their effects on bone homeostasis have been proposed. This review highlights recent work on physiological bone remodeling and discusses our knowledge, as it currently stands, on the systemic interplay of factors regulating this interaction. In this review, we provide a summary of the literature on the relationship between bone physiology and hormones including kisspeptin, neuropeptide Y, follicle-stimulating hormone (FSH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), leptin, and adiponectin. The discovery and understanding of this new functionality unveils an entirely new layer of physiologic circuitry.

The objective of this systematic review was to determine the current state of the literature regarding how adipocytokines associate with mental health symptoms/disorders in youth. Findings summarized in this review suggested that in neurodevelopmental disorders, higher levels of leptin, ghrelin, resistin, and visfatin as well as lower levels of adiponectin, retinol-binding protein 4, and progranulin predicted increased risk for or were conflated with autism spectrum disorder. Adipocytokine correlates of attention-deficit hyperactivity disorder and related symptoms included higher apelin, higher leptin-to-adiponectin ratio, and lower adiponectin. Evidence from studies examining anxiety symptoms evinced mixed results regarding leptin, and one study suggested higher levels of ghrelin. Depressive symptoms correlated with higher leptin and ghrelin. Research examining posttraumatic stress symptoms found higher levels of ghrelin. In research examining broadband symptoms, conflicting results emerged for associations between internalizing symptoms (i.e., symptoms of emotional stress) and leptin in youth. Low levels of adiponectin and high levels of leptin predicted externalizing symptoms. Total symptom difficulties were associated with a higher leptin-to-adiponectin ratio. Our findings suggest that adipocytokines may be an important set of biomarkers to consider as underlying mechanisms contributing to developmental psychopathology.

Traumatic stress disorders are defined in part by persistent avoidance of trauma-related contexts. Our lab uses a preclinical model of traumatic stress using predator odor (i.e., bobcat urine) in which some but not all rats exhibit persistent avoidance of odor-paired stimuli, similar to what is seen in humans. Bobcat urine exposure increases alcohol consumption in male Avoider rats, but it has not been tested for its effects on intake of other drugs. Here, we tested the effect of bobcat urine exposure on cocaine self-administration in adult male and female Wistar rats. We did not observe any effect of bobcat urine exposure on cocaine self-administration in male or female rats. We observed that (1) female rats with long access (6 hours) to cocaine self-administer more cocaine than long-access males, (2) long-access males and females exhibit escalation of cocaine intake over time, (3) stressed rats gain less weight than unstressed rats following acute predator odor exposure, (4) baseline cocaine self-administration is predictive of subsequent cocaine self-administration. The results of this study may inform future work on predator odor effects on cocaine self-administration.

Gut microbiota is of great importance in human health, and its roles in the maintenance of skeletal homeostasis have long been recognized as the "gut-bone axis." Recent evidence has indicated intercorrelations between gut microbiota, endocrine system and bone metabolism. This review article discussed the complex interactions between gut microbiota and bone metabolism-related hormones, including sex steroids, insulin-like growth factors, 5-hydroxytryptamine, parathyroid hormone, glucagon-like peptides, peptide YY, etc. Although the underlying mechanisms still need further investigation, the regulatory effect of gut microbiota on bone health via interplaying with endocrine system may provide a new paradigm for the better management of musculoskeletal disorders.