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This study explored the effects of prenatal exposure to fumonisins B (FB) on bone innervation in newborn Wistar rats.

The effect of the nervous system on bone remodelling has been described by many studies. Sensory and autonomic nerves are present in the bone. Immunohistochemical analysis of the bone have indicated the presence of neuropeptides and neurotransmitters that act on bone cells through receptors. Besides carrying sensory information, sensory neurons produce various neuropeptides playing an important role in maintaining bone and tooth pulp homeostasis, and dentin formation. Bone tissue and teeth contain organic and inorganic components. Bone cells enable bone mineralization and ensure its formation and resorption. Studies focused on the effects of the nervous system on the bone are proceeded using various ways. Sensory denervation itself can be achieved using capsaicin causing chemical lesion to the nerve. Surgical ways of causing only sensory lesion to nerves are substantially limited because many peripheral nerves are mixed and contain a motor component as well. From this point of view, the experimental model with transection of inferior alveolar nerve is appropriate. This nerve provides sensory innervation of the bone and teeth of the mandible. The purpose of our paper is to provide an overview of the effects exerted by the nervous system on the inorganic component of the bone and teeth, and also to present an overview of the used experimental models. As we assume, the transection of inferior alveolar nerve could be reflected in changed contents and distribution of chemical elements in the bone and teeth of rat mandible. This issue has not been studied so far.

In contrast to the vast majority of reptiles, the skulls of adult crown birds are characterized by a high degree of integration due to bone fusion, e.g., an ontogenetic event generating a net reduction in the number of bones. To understand this process in an evolutionary context, we investigate postnatal ontogenetic changes in the skulls of crown bird and non-avian theropods using anatomical network analysis (AnNA). Due to the greater number of bones and bone contacts, early juvenile crown birds have less integrated skulls, resembling their non-avian theropod ancestors, including Archaeopteryx lithographica and Ichthyornis dispars. Phylogenetic comparisons indicate that skull bone fusion and the resulting modular integration represent a peramorphosis (developmental exaggeration of the ancestral adult trait) that evolved late during avialan evolution, at the origin of crown-birds. Succeeding the general paedomorphic shape trend, the occurrence of an additional peramorphosis reflects the mosaic complexity of the avian skull evolution. Plateau and Foth use anatomical network analysis to study the evolution of avian skull anatomy. They report that the ontogenetic changes in the morphology and modularity of the avian skulls is comparable to evolutionary transformations from non-avian theropods to modern birds. Their work highlights the complexity of avian skull evolution. [ABSTRACT FROM AUTHOR]

An increase of fracture incidence is expected for the next decades, mostly due to the undeniable increase of osteoporotic fractures, associated with the rapid population ageing. The rise in sports-related fractures affecting the young and active population also contributes to this increased fracture incidence, and further amplifies the economical burden of fractures. Fracture often results in severe pain, which is a primary symptom to be treated, not only to guarantee individual's wellbeing, but also because an efficient management of fracture pain is mandatory to ensure proper bone healing. Here, we review the available data on bone innervation and its response to fracture, and discuss putative mechanisms of fracture pain signaling. In addition, the common therapeutic approaches to treat fracture pain are discussed. Although there is still much to learn, research in fracture pain has allowed an initial insight into the mechanisms involved. During the inflammatory response to fracture, several mediators are released and will putatively activate and sensitize primary sensory neurons, in parallel, intense nerve sprouting that occurs in the fracture callus area is also suggested to be involved in pain signaling. The establishment of hyperalgesia and allodynia after fracture indicates the development of peripheral and central sensitization, still, the underlying mechanisms are largely unknown. A major concern during the treatment of fracture pain needs to be the preservation of proper bone healing. However, the most common therapeutic agents, NSAIDS and opiates, can cause significant side effects that include fracture repair impairment. The understanding of the mechanisms of fracture pain signaling will allow the development of mechanisms-based therapies to effectively and safely manage fracture pain. [ABSTRACT FROM AUTHOR]

Although bone pain caused by cancer chemotherapy is a well-recognized and significant problem, with approximately 1 in 10 childhood cancer patients being reported to experience isolated bone pain along with other skeletal complications, the underlying mechanisms are poorly understood and there is no specific treatment. In this study, effects of methotrexate (MTX) treatment on pain in the hind legs and the extent of sensory innervation of the tibial bone were examined through a 20-day time course in young rats after 5 daily 0.75 mg/kg MTX injections. MTX treatment increased von-Frey filament stimulation-induced mechanical allodynia and palpation nocifensive score in the tibia. MTX-treated rats showed trends in reduced loading (numbers of stands) on hind limbs after palpation, commencing early during treatment and 2 weeks after the end of treatment despite no signs of ongoing pain during normal locomotion. Immunohistochemical analyses showed an increase in innervation of calcitonin gene-related peptide (CGRP)-positive sensory nerve fibres in tibial periosteum on days preceding and overlapping with those rats with touch-evoked pain responses and the bone repair phase. These data suggest that methotrexate chemotherapy triggers touch-evoked pain involving enhanced sensory nerve innervation of the bone. [ABSTRACT FROM AUTHOR]

Bone pain is one of the most frequent kinds of chronic pain, mainly in elderly patients. It causes a significant worsening of functional capacity and deterioration in the quality of life in people affected. Mechanisms of pain in osteoporosis are poorly known and often extrapolated by other pathologies or other experimental model. One of principal causes would be a "hyper-remodeling" of bone, that involves osteoclasts activity and pathological modifications of bone innervation. Several studies show that osteoclasts play a significant role in bone pain etiology. Pain in osteoporosis is mainly nociceptive, if it become persistent a sensitization of peripheral and central nervous system can occur, so underlining the transition to a chronic pain syndrome. Central sensitization mechanisms are complex and involve several neuromediators and receptors (Substance P, NMDA, etc.). Most common manifestations of osteoporosis are vertebral compression fractures that cause persistent pain, though to differentiate from pain originating in structures as joint or muscle. First manifestation can be an acute pain due to pathological fracture, those of hip often causes disability. Pain in osteoporosis is an important clinical challenge. Often its complications and consequences on patient quality of life are underestimated with not negligible social implications. A balanced and early multimodal pain therapy including opioids as necessary, even in cases of acute pain, improve the functional capacity of patients and helps to prevent neurological alterations that seems to contribute in significant way in causing irreversible pain chronic syndromes. [ABSTRACT FROM AUTHOR]

Background and aims: Elderly individuals who suffer a fracture develop a gait disturbance and require prolonged bedrest. A fracture has a massive impact both physically and mentally and markedly diminishes quality of life. A new form of therapeutic exercise that mitigates the abrupt decrease in bone density in postmenopausal women must soon be developed so that those problems can be avoided. Methods: The current study used a model of the decrease in bone density in ovariectomized mice to simulate postmenopausal women. The stimulus was provided by a shaking horizontal platform rotating in a circular motion. Results: Comparison of the +/+ (ovariectomized/stimulated) group and +/− group indicated a significant decrease in BV/TV ( p < 0.01), Tb.Th ( p < 0.01), and Tb.N ( p < 0.05) in the +/+ group and a significant increase in OV/BV ( p < 0.01), OV/OS ( p < 0.01), BFR/BV ( p < 0.01), dLS/BS ( p < 0.05), MS/BS ( p < 0.05), BRs.R ( p < 0.01), and Tb.Sp ( p < 0.01) in the +/+ group. Physical therapy to prevent a decrease in bone density was studied via stimulus in the form of rotation of a platform. Analysis of bone histomorphometry revealed lessening of the decrease in bone density of the lumbar vertebrae, a feat that the stimulus from conventional physical therapy had failed to achieve. Conclusion: The current study delivered a shaking stimulus to mice in a model of postmenopause. Analysis of bone histomorphometry of the lumbar vertebrae suggested lessening of the abrupt decrease in bone density of trabecular bone. If this finding is used clinically, it could lead to physical therapy exercise that would be able to prevent compression fractures of the lumbar vertebrae. [ABSTRACT FROM AUTHOR]

Accumulating evidence has contributed to a novel view in bone biology: bone remodeling, specifically osteoblast differentiation, is under the tight control of the central and peripheral nervous systems. Among other players in this neuro-osteogenic network, the neuropeptide Y (NPY) system has attracted particular attention. At the central nervous system level, NPY exerts its function in bone homeostasis through the hypothalamic Y2 receptor. Locally in the bone, NPY action is mediated by its Y1 receptor. Besides the presence of Y1, a complex network exists locally: not only there is input of the peripheral nervous system, as the bone is directly innervated by NPY-containing fibers, but there is also input from non-neuronal cells, including bone cells capable of NPY expression. The interaction of these distinct players to achieve a multilevel control system of bone homeostasis is still under debate. In this review, we will integrate the current knowledge on the impact of the NPY system in bone biology, and discuss the mechanisms through which the balance between central and the peripheral NPY action might be achieved. [ABSTRACT FROM AUTHOR]

The article discusses a study that examined bone formation in several bones responding to weight and determine whether or not adaptation may be regulated by neurons. The left and right ulnas and humeri bones in rats were loaded and given calcein after one period of loading to label new bone formation. It was found that functional adaptation to loading of a single bone in young rats is neuronally regulated and involves multiple bones. Information is given for plasticity in bone innervation.

Although the responses of bone to increased loading or exercise have been studied in detail, our understanding of the effects of decreased usage of the skeleton has been limited by the scarcity of suitable models. Such models should ideally not affect bone innervation, which appears to be a mediator of physiological responses of bone to unloading. MyoD–/–/Myf5–/– (dd/ff) mice lack skeletal muscle, so the fetuses develop without any active movement in utero and die soon after birth. We used micro-compter tomography and histology to analyse their bone development and structure during endochondral ossification in parallel with the establishment of bone innervation. Long bones from mutant mice were found to be profoundly different from controls, with shorter mineralized zones and less mineralization. They lacked many characteristics of adult bones – curvatures, changes in shaft diameter and traction epiphyses where muscles originate or insert – that were evident in the controls. Histologically, dd/ff mice showed the same degree of endochondral development as wild-type animals, but presented many more osteoclasts in the newly layed bone. Innervation and the expression pattern of semaphorin-3A signalling molecules were not disturbed in the mutants. Overall, we have found no evidence for a major defect of development in dd/ff mice, and specifically no alteration or delay in endochondral ossification and bone innervation. The altered morphological features of dd/ff mice and the increased bone resorption show the role of muscle activity in bone shaping and the consequences of bone unloading. [ABSTRACT FROM AUTHOR]

Sympathetic innervation has been demonstrated in bone. Adrenergic stimulation is one of the transmitters of bone loss by uncoupling between decreased bone formation and increased bone resorption.Objective. – By using a non specific antagonist of β-adrenergic pathway (propranolol per os), we hypothesized that we could rescue the uncoupling induced mechanical unloading bone loss in the rat model of tail-suspension.Materials and methods. – Twenty-two female rats Wistar, 12 week-old, have been divided into three groups: eight tail-suspended rats (SR), six tail-suspended rats treated by propranolol (SRP) and eight non suspended rats (NSR) during 30 days. Bone mineral density (BMD, g/cm2) has been measured by DXA (Hologic QDR-4500A) at D0 and D30 of the study, in the distal femoral metaphysis (DFM), the femoral diaphysis (FD), the whole body (WB, g) and body composition.Results. – Between D0 and D30, in DFM a significant variation in BMD is observed between NSR and SR (% BMD change: NSR +15.6 ± 3.1% vs. SR –1.0 ± 1.4%, P < 0.0001) and BMD rescue in SRP group (% BMD change SRP +5.3 ± 1.5% vs. SR –1.0 ± 1.4%, P = 0.03). In FD, gain of BMD is significant in NSR compared to SR (+17.5 ± 1.5% vs. +8.2 ± 2.8%, P = 0.007), and to SRP (+17.5 ± 1.5% vs + 10.1 ± 2.4%, P = 0.046). Gain in SRP group is not significant compared to SR group (P = 0.6). In WB SRP gain more BMD than NSR (+14.0 ± 1.8% vs. +5.4 ± 0.7%, P = 0.0002) and than SR (+14.0 ± 1.8% vs. +7.8 ± 1.4%, P = 0.0043). There is no difference between NSR and SR groups (P = 0.19).Conclusion. – We demonstrate that β-adrenergic pathway of sympathetic nervous system is a major transmitter pathway of mechanical loading in rat bone. A specific study is necessary to analyse a possible systemic effect of propranolol in rat bone. Propranolol could be used to prevent induced mechanical unloading bone loss as weightlessness. [Copyright &y& Elsevier]

Pain in degenerative bone and joint disease is usually attributed to sensitized nociceptors in inflamed periarticular soft tissues. Here we draw attention to the potential contribution of intrinsic bone innervation. The structure and innervation of articular bone ends is analogous to that of teeth. Although some dental pain derives from inflamed periodontal soft tissue, a more important source is the dentine and root canal. By analogy, pain on weight bearing in osteoarthritis and related conditions may be due to compressive forces applied to the innervation of subchondral bone exposed by erosion of the overlying cartilage. Pain relief obtained by injecting acrylic cement into the bone interior during percutaneous vertebroplasty is consistent with this concept. The development of a new family of pain relief options based on “marrow canal treatment” may be a realistic possibility. [Copyright &y& Elsevier]

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Simple Summary: Multiple myeloma is a bone marrow cancer that often causes bone pain, but little is known about the pain characteristics and mechanisms in this condition. This clinical study aims to: 1. characterize the type, location and intensity of pain in myeloma patients, and its effect of quality of life, and 2. investigate whether the nerve fibers in the bone of myeloma patients are altered. We will also explore whether pain intensity is correlated to blood indicators of inflammation or bone damage. Study results will help identify the mechanisms of myeloma-induced bone pain, allowing the development of new analgesics for these patients. Multiple myeloma (MM) is a bone marrow neoplasia that causes bone pain in 70% patients. While preclinical models of MM have suggested that both nerve sprouting and nerve injury may be causative for the pain, there is a lack of clinical data. Thus, the primary aims of this clinical study are: (1) to provide a deep characterization of the subjective experience of pain and quality of life in MM patients; (2) to investigate disturbances in the bone innervation of MM patients. Secondary aims include exploring correlations between pain and serum inflammatory and bone turnover biomarkers. In a prospective, observational study (clinicaltrials.gov: NCT04273425), patients with suspected MM requiring a diagnostic iliac crest biopsy at Sheffield Teaching Hospital (UK) are invited to participate. Consenting patients answer seven standardized questionnaires assessing pain, quality of life and catastrophizing. Bone turnover biomarkers and inflammatory cytokines are measured in fasting serum samples, and bone innervation is evaluated in diagnostic biopsies. MM patients are invited to a follow-up upon completion of first line treatment. This will be the first deep characterization of pain in MM patients and its correlation with disturbances in bone innervation. Understanding how bone turnover and inflammation correlate to pain in MM is crucial to identify novel analgesic targets for this condition. [ABSTRACT FROM AUTHOR]

Background: Sciuromorpha (squirrels and close relatives) are diverse in terms of body size and locomotor behavior. Individual species are specialized to perform climbing, gliding or digging behavior, the latter being the result of multiple independent evolutionary acquisitions. Each lifestyle involves characteristic loading patterns acting on the bones of sciuromorphs. Trabecular bone, as part of the bone inner structure, adapts to such loading patterns. This network of thin bony struts is subject to bone modeling, and therefore reflects habitual loading throughout lifetime. The present study investigates the effect of body size and lifestyle on trabecular structure in Sciuromorpha. Methods: Based upon high-resolution computed tomography scans, the femoral head 3D inner microstructure of 69 sciuromorph species was analyzed. Species were assigned to one of the following lifestyle categories: arboreal, aerial, fossorial and semifossorial. A cubic volume of interest was selected in the center of each femoral head and analyzed by extraction of various parameters that characterize trabecular architecture (degree of anisotropy, bone volume fraction, connectivity density, trabecular thickness, trabecular separation, bone surface density and main trabecular orientation). Our analysis included evaluation of the allometric signals and lifestyle-related adaptation in the trabecular parameters. Results: We show that bone surface density, bone volume fraction, and connectivity density are subject to positive allometry, and degree of anisotropy, trabecular thickness, and trabecular separation to negative allometry. The parameters connectivity density, bone surface density, trabecular thickness, and trabecular separation show functional signals which are related to locomotor behavior. Aerial species are distinguished from fossorial ones by a higher trabecular thickness, lower connectivity density and lower bone surface density. Arboreal species are distinguished from semifossorial ones by a higher trabecular separation. Conclusion: This study on sciuromorph trabeculae supplements the few non-primate studies on lifestyle-related functional adaptation of trabecular bone. We show that the architecture of the femoral head trabeculae in Sciuromorpha correlates with body mass and locomotor habits. Our findings provide a new basis for experimental research focused on functional significance of bone inner microstructure. [ABSTRACT FROM AUTHOR]