Innervation Of Bone Research Articles

Emerging roles of nerve-bone axis in modulating skeletal system.

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.

THU453 Chronic Headaches As A Presentation For Monostotic Craniofacial Fibrous Dysplasia: A Case Study

Abstract Disclosure: B. Dyer: None. R.K. Bhattacharya: None. Background: Monostotic craniofacial fibrous dysplasia (CFFD) is often asymptomatic and is found incidentally on imaging. Previous reports described cases in which CFFD diagnosis was preceded by chronic headaches, but there remains a lack of clinical association between these diagnoses. Clinical Case: Patient is a 22-year-old female with a long history of chronic headaches who presented to the emergency department two days after a motor vehicle accident with complaints of headache, blurred vision, nausea, and dizziness. CT revealed an incidental sclerotic mass in the left frontal region measuring 7.9x7.3x3.7cm extending inferiorly into the left ethmoid sinus. At her primary care follow-up, she reported a pounding, left-sided headache in addition to balance issues, dizziness, nausea, and blurry vision. Workup was significant for vitamin D level of 11.2ng/mL (n = 30-100ng/mL), alkaline phosphate of 106U/L (n = 35-104U/L), and calcium of 9.1mg/dL (n = 8.6-10.3mg/dL). MRI was significant for a heterogeneous, hypointense expansile calvarial lesion within the left frontal and left sphenoid bones. The patient was diagnosed with CFFD based on radiologic findings. The patient was advised against surgical intervention due to her disease’s large, invasive nature. The patient was seen by neurology for recurrent headaches and was subsequently started on topiramate with partial symptom relief. Endocrinologist management included confirmation of monostotic CFFD by bone scan. Biopsy was deferred due to the low likelihood of malignant transformation, and bisphosphonate treatment was initiated. She was subsequently started on 5000 IU per day of vitamin D to normalize the vitamin D level before the initiation of bisphosphonate treatment for her pain. She received 5mg intravenous infusion of zoledronic treatment. At follow-up, the patient states she had significant improvement in all symptoms. Conclusion: Pain from FD can be debilitating and often increases in severity as the patient ages, though pain is not strongly correlated to presentation or disease burden. The mechanism by which CFFD produces pain is not fully elucidated. The unique innervation of bone and the creation of new sensory nerve fibers during inflammatory states may contribute. Additionally, excess IL-6 during inflammatory states may also play a role in pain production due to lesion expansion from osteoclast activation, cystic formation within the lesion, and hormonal reactivity of the lesion. Bisphosphonates are believed to inhibit IL-6 production, reducing osteoclastic activity and leading to symptomatic pain relief. In the case presented, the patient’s chronic headaches improved significantly following combination therapy with migraine abortive medication and bisphosphonate therapy. Early recognition and multidisciplinary treatment are key in the long-term management of CFFD pain. Presentation: Thursday, June 15, 2023

Identification of Functional Modules and Key Pathways Associated with Innervation in Graft Bone-CGRP Regulates the Differentiation of Bone Marrow Mesenchymal Stem Cells via p38 MAPK and Wnt6/β-Catenin.

Bone resorption occurs after bone grafting, however, contemporaneous reconstruction of the innervation of the bone graft is a potential treatment to maintain the bone mass of the graft. The innervation of bone is an emerging research topic. To understand the potential molecular mechanisms of bone innervation after bone grafting, we collected normal iliac bone tissue as well as bone grafts with or without innervation from nine patients 1 year after surgery and performed RNA sequencing. We identified differentially expressed genes) from these samples and used the gene ontology and Kyoto Encyclopedia of Genes and Genomes databases for functional enrichment and signaling pathway analysis. In parallel, we established protein-protein interaction networks to screen functional modules. Based on bioinformatic results, we validated in vitro the osteogenic differentiation potential of rat bone marrow mesenchymal stem cells (BMMSCs) after calcitonin gene-related peptide (CGRP) stimulation and the expression of p38 MAPK and Wnt6/β-catenin pathways during osteogenesis. Our transcriptome analysis of bone grafts reveals functional modules and signaling pathways of innervation which play a vital role in the structural and functional integration of the bone graft. Simultaneously, we demonstrate that CGRP regulates the differentiation of BMMSCs through p38 MAPK and Wnt6/β-catenin.

What's New in Musculoskeletal Basic Science.

What's New in Musculoskeletal Basic Science.

Nerves in Bone: Evolving Concepts in Pain and Anabolism.

ABSTRACTThe innervation of bone has been described for centuries, and our understanding of its function has rapidly evolved over the past several decades to encompass roles of subtype‐specific neurons in skeletal homeostasis. Current research has been largely focused on the distribution and function of specific neuronal populations within bone, as well as their cellular and molecular relationships with target cells in the bone microenvironment. This review provides a historical perspective of the field of skeletal neurobiology that highlights the diverse yet interconnected nature of nerves and skeletal health, particularly in the context of bone anabolism and pain. We explore what is known regarding the neuronal subtypes found in the skeleton, their distribution within bone compartments, and their central projection pathways. This neuroskeletal map then serves as a foundation for a comprehensive discussion of the neural control of skeletal development, homeostasis, repair, and bone pain. Active synthesis of this research recently led to the first biotherapeutic success story in the field. Specifically, the ongoing clinical trials of anti‐nerve growth factor therapeutics have been optimized to titrated doses that effectively alleviate pain while maintaining bone and joint health. Continued collaborations between neuroscientists and bone biologists are needed to build on this progress, leading to a more complete understanding of neural regulation of the skeleton and development of novel therapeutics. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

Sclerotomes: A Comprehensive Review of the Innervation of Bone

Sclerotomes: A Comprehensive Review of the Innervation of Bone

The Central Nervous System and Bone Metabolism: An Evolving Story.

Our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by our understanding of energy metabolism. Evidence demonstrating that leptin not only influences bone cells directly, but that it also plays a pivotal role in controlling bone mass centrally, opened up an investigative process that has changed the way in which skeletal metabolism is now perceived. Other central regulators of bone metabolism have since been identified including neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U, controlling osteoblast and osteoclast differentiation, proliferation and function. The sympathetic nervous system was originally identified as the predominant efferent pathway mediating central signalling to control skeleton metabolism, in part regulated through circadian genes. More recent evidence points to a role of the parasympathetic nervous system in the control of skeletal metabolism either through muscarinic influence of sympathetic nerves in the brain or directly via nicotinic receptors on osteoclasts, thus providing evidence for broader autonomic skeletal regulation. Sensory innervation of bone has also received focus again widening our understanding of the complex neuronal regulation of bone mass. Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the multiple confounders influencing skeletal metabolism, and the relative balance in these neuronal systems required for skeletal growth and development in childhood and maintaining skeletal integrity in adulthood.

Methotrexate chemotherapy triggers touch-evoked pain and increased CGRP-positive sensory fibres in the tibial periosteum of young rats

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 0.75mg/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 2weeks 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.

The effect of diabetic neuropathy on foot bones: a systematic review and meta‐analysis

It is proposed that diabetic neuropathy may affect peripheral bone. Direct innervation of bone as well as neural control over its vascular supply and muscular influences may be affected by diabetes-induced peripheral neuropathies. Associated changes to bone may contribute to the occurrence of foot bone pathology in this population. This systematic review aims to examine the literature related to the effect of diabetic neuropathy on foot bones. Studies examining relationships between neuropathy and indicators of bone health (e.g. bone mineral density) in populations with diabetes were sought. Relevant publications were obtained from searches in MEDLINE, CINAHL and Embase in the period up to March 2013. Meta-analysis was performed using a random effects model in the statistical package Stata version 12.1. Ten studies met the inclusion criteria and were included in the narrative synthesis. All studies were cross-sectional or case-control in design. Four of the 10 included studies found results indicating poorer bone health in those with diabetes and neuropathy compared with those with diabetes without neuropathy. Seven of the 10 studies were able to be included in a meta-analysis. The mean pooled effect was -0.36 (95% CI -0.76 to 0.04; P = 0.08), indicating a non-significant trend towards poorer bone health in those with diabetic neuropathy. We did not find a significant relationship between presence of neuropathy in those with diabetes and poorer peripheral bone health. However, methodological limitations of the included studies mean further research is required to investigate this theoretical relationship.

The role of the sensory nerve response in ultrasound accelerated fracture repair

This study was designed to test the hypothesis that the sensory innervation of bone might play an important role in sensing and responding to low-intensity pulsed ultrasound and explain its effect in promoting fracture healing. In 112 rats a standardised mid-shaft tibial fracture was created, supported with an intramedullary needle and divided into four groups of 28. These either had a sciatic neurectomy or a patellar tendon resection as control, and received the ultrasound or not as a sham treatment. Fracture union, callus mineralisation and remodelling were assessed using plain radiography, peripheral quantitative computed tomography and histomorphology. Daily ultrasound treatment significantly increased the rate of union and the volumetric bone mineral density in the fracture callus in the neurally intact rats (p = 0.025), but this stimulating effect was absent in the rats with sciatic neurectomy. Histomorphology demonstrated faster maturation of the callus in the group treated with ultrasound when compared with the control group. The results supported the hypothesis that intact innervation plays an important role in allowing low-intensity pulsed ultrasound to promote fracture healing.

The NPY System and its Neural and Neuroendocrine Regulation of Bone

The past decade has seen a significant expansion of our understanding of the interaction between the neural system and bone. While innervation of bone was long appreciated, the discovery of central relays from the hypothalamus to the cells of bone has seen the identification of a number of efferent neural pathways to bone. The neuropeptide Y (NPY) system has proven to represent a major central pathway, regulating the activity of osteoblasts and osteoclasts, through signaling of central and peripheral ligands, through specific receptors within the hypothalamus and the osteoblast. Moreover, this pathway is now recognized as acting to coordinate both skeletal and energy homeostasis. This review examines the mechanism and actions of the NPY pathway to regulate bone mass and bone cell activity.

The effect of aging on the density of the sensory nerve fiber innervation of bone and acute skeletal pain

As humans age there is a decline in most sensory systems including vision, hearing, taste, smell, and tactile acuity. In contrast, the frequency and severity of musculoskeletal pain generally increases with age. To determine whether the density of sensory nerve fibers that transduce skeletal pain changes with age, calcitonin gene related peptide (CGRP) and neurofilament 200 kDa (NF200) sensory nerve fibers that innervate the femur were examined in the femurs of young (4-month-old), middle-aged (13-month-old) and old (36-month-old) male F344/BNF1 rats. Whereas the bone quality showed a significant age-related decline, the density of CGRP+ and NF200+ nerve fibers that innervate the bone remained remarkably unchanged as did the severity of acute skeletal fracture pain. Thus, while bone mass, quality, and strength undergo a significant decline with age, the density of sensory nerve fibers that transduce noxious stimuli remain largely intact. These data may in part explain why musculoskeletal pain increases with age.

Adipose tissue – A new window of insight into bone remodelling?

Fat grafts transplanted into surgically created bone defects inhibit local bone regeneration. This phenomenon is employed to good effect by surgeons. In neurosurgery, fat grafts prevent constriction of the spinal cord by laminectomy membrane composed of scar tissue and bony callus. Also, following the resection of a seg- ment of ulnar diaphysis or a transphyseal bone bridge in growing dogs and children, the inser- tion of a fat graft prevents the local regener- ation of bone; effectively producing a localised atrophic non-union and allowing continued bone growth (1,2). Since fat grafts are composed mainly of adipocytes embedded in a sparse fibrous stroma, it has been assumed that a piece of fat filling a bony void simply prevents the ingrowth of fibrovascular tissue and subse- quent bone callus formation. As orthopaedic surgeons, this appreciation Mechanical loading is a very major factor regulating bone remodelling in skeletally ma- ture animals, but leptin also has some role in regulating bone mass. Leptin acts directly on bone cells and bone marrow stem cells, and indirectly via the hypothalamic-sympathetic nervous system to alter bone mass (4). Leptin receptors are present in the hypothalamus, and receptor-bound leptin blocks sympath- etic innervation of bone. Sympathetic nerve fibres are widely and non-uniformly dis- tributed over bone surfaces, and normally the release of noradrenaline from sympathetic fibres projecting onto bone inhibits bone formation. Thus elevated levels of leptin may act centrally, and indirectly result in bone proliferation. Although these interactions are quite complex, a growing body of knowledge provides us with a whole new window of in- sight into the understanding the 'non- loading' mechanisms that control bone re- modelling. These neuro-endocrine mech- anisms are probably important in regulating normal bone remodelling in 'non-loaded' limb bones such as the upper limb in bipedal animals. Also, they might be involved in the development of certain idiopathic bone dis- eases. For example, animals and people suf- fering from secondary hypertrophic oste- opathy (Marie's Disease) have bilaterally symmetrical periosteal bone formed along the diaphyses of the limb bones, in conjunc- tion with intra-thoracic pathology. Often the bone proliferation on the limbs will inexplic- ably regress after resection of the intra-tho- racic lesion, suggesting that some type of neuro-endocrine mechanism is responsible for the bone proliferation. Certainly it is grat- ifying to appreciate how research into the growing epidemic of obesity has serendipi- tously revealed so much new knowledge about the regulation of bone remodelling.

Functional Adaptation to Loading of a Single Bone Is Neuronally Regulated and Involves Multiple Bones

Regulation of load-induced bone formation is considered a local phenomenon controlled by osteocytes, although it has also been hypothesized that functional adaptation may be neuronally regulated. The aim of this study was to examine bone formation in multiple bones, in response to loading of a single bone, and to determine whether adaptation may be neuronally regulated. Load-induced responses in the left and right ulnas and humeri were determined after loading of the right ulna in male Sprague-Dawley rats (69 +/- 16 days of age). After a single period of loading at -760-, -2000-, or -3750-microepsilon initial peak strain, rats were given calcein to label new bone formation. Bone formation and bone neuropeptide concentrations were determined at 10 days. In one group, temporary neuronal blocking was achieved by perineural anesthesia of the brachial plexus with bupivicaine during loading. We found right ulna loading induces adaptive responses in other bones in both thoracic limbs compared with Sham controls and that neuronal blocking during loading abrogated bone formation in the loaded ulna and other thoracic limb bones. Skeletal adaptation was more evident in distal long bones compared with proximal long bones. We also found that the single period of loading modulated bone neuropeptide concentrations persistently for 10 days. We conclude that functional adaptation to loading of a single bone in young rapidly growing rats is neuronally regulated and involves multiple bones. Persistent changes in bone neuropeptide concentrations after a single loading period suggest that plasticity exists in the innervation of bone.

The evidence for the spinal segmental innervation of bone

Dermatomes and myotomes are areas of skin and muscle, respectively, that are innervated by single spinal segmental nerves, and reflect a principle of organization that appears in just about every clinical textbook available today. The evidence for the existence of dermatomes and myotomes has a long and substantial history. A lesser known, but similar principle exists for the skeletal system. The term "sclerotome" was first used in the non-embryological sense by Inman and Saunders ([1944] J. Nerv. Ment. Dis. 99:660-667) to define a region of bone and periosteum that is innervated by a single spinal segment. It is used by clinicians in many healthcare settings to aid in the diagnosis and description of a variety of deep and/or skeletal tissue pathologies and pain syndromes. In this article, the evidence for the existence of the sclerotomes is described in detail. Early clinical studies that define the sclerotomes, evidence from studies of the development of skeletal innervation, and the contributions of anatomical and physiological investigations are explored. It is suggested that there is in fact little direct evidence for the existence of discrete spinal segmental innervation patterns for the skeleton.

A Blocking Antibody to Nerve Growth Factor Attenuates Skeletal Pain Induced by Prostate Tumor Cells Growing in Bone

Prostate cancer is unique in that bone is often the only clinically detectable site of metastasis. Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully control as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and some neuropathic pain states in animal models, an NGF-sequestering antibody was administered in a prostate model of bone cancer where significant bone formation and bone destruction occur simultaneously in the mouse femur. Administration of a blocking antibody to NGF produced a significant reduction in both early and late stage bone cancer pain-related behaviors that was greater than or equivalent to that achieved with acute administration of 10 or 30 mg/kg of morphine sulfate. In contrast, this therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. One rather unique aspect of the sensory innervation of bone, that may partially explain the analgesic efficacy of anti-NGF therapy in relieving prostate cancer-induced bone pain, is that nearly all nerve fibers that innervate the bone express trkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors. The present results suggest that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor-induced bone cancer pain.

Introduction to the innervation of bone.

Microscopy Research and TechniqueVolume 58, Issue 2 p. 59-60 Topical Paper Introduction to the innervation of bone Tetsuya Goto, Tetsuya Goto Guest Editor Department of Oral Anatomy, Kyushu Dental College, Kitakyushu 803-8580 JapanSearch for more papers by this author Tetsuya Goto, Tetsuya Goto Guest Editor Department of Oral Anatomy, Kyushu Dental College, Kitakyushu 803-8580 JapanSearch for more papers by this author First published: 23 July 2002 https://doi.org/10.1002/jemt.10113Citations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume58, Issue2Special Issue: The Innervation of Bone15 July 2002Pages 59-60 RelatedInformation

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

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

The regulation of connective tissue metabolism by vasoactive intestinal polypeptide

Immunohistochemical studies have confirmed the innervation of bone with neuropeptidergic neurons containing vasoactive intestinal polypeptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). In this study, we report effects of VIP on connective tissue cell metabolism. VIP stimulated PGE 2 production in human articular chondrocytes, human osteoblast-like cells and human synovial cells, however, stromelysin production was unaffected. VIP also stimulated cAMP production in human osteoblast-like cells, but not in human articular chondrocytes or synovial cells. These findings are suggestive of a role of VIP in connective tissue cell metabolism which may contribute to the inflammatory processes of arthritis.

Effect of guanethidine-induced sympathectomy on osteoblastic activity in the rat femur evaluated by 3H-proline autoradiography.

Osteoblastic activity in the rat femur was assessed following sympathectomy by injections of guanethidine sulfate from birth to 14 days of age. At ages 30, 45 and 90 days, osteogenesis was monitored by quantitative autoradiography using 3H-proline. Grain counts over periosteal osteoblasts of the femoral diaphysis showed a significant reduction in the uptake of 3H-proline in sympathectomized rats. The results indicate that the sympathetic innervation of bone influences osteoblastic activity and provide support for a role of the autonomic nervous system in the regulation of bone formation.