Innervation of human bone periosteum by peptidergic nerves

Grönblad, Mats; Liesi, Päivi; Korkala, O; Karaharju, Erkki; Polak, Julia M.

doi:10.1002/ar.1092090306

Cited by 94 publications

(58 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the present report we demonstrate that, in contrast to sensory fibers that innervate the marrow or mineralized bone [4,7,11,14] as well as sympathetic fibers that innervate the marrow, mineralized bone and periosteum, sensory fibers that innervate the periosteum are organized in a distinct net-like meshwork and these periosteal sensory fibers frequently lack association with CD31+ blood vessels. Given this unique organization, a key question is whether this organization has functional significance and if so whether it sheds light on the human perception of pain following skeletal fracture.…”

Section: Cambium Layermentioning

confidence: 44%

Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum: Implications for the generation and maintenance of bone fracture pain

Martin

Jiménez-Andrade

Ghilardi

et al. 2007

Neuroscience Letters

101

View full text Add to dashboard Cite

Although bone fracture frequently results in significant pain and can lead to increased morbidity and mortality, it is still not clearly understood how sensory neurons are organized to detect fracture pain. In the present report we focused on the periosteum, as this thin tissue is highly innervated and tightly adherent to the outer surface of bone. To define the organization and distribution of the sensory and sympathetic fibers in the mouse femoral periosteum, we used whole mount preparations, transverse sections, immunofluoresence, and laser scanning confocal microscopy. While both the outer fibrous layer and the inner more cellular cambium layer of the periosteum receive an extensive innervation by calcitonin gene related peptide (CGRP) and 200-kDa neurofilament (NF200) positive sensory fibers as well as tyrosine hydroxylase (TH) positive sympathetic fibers, there is a differential organization of sensory vs. sympathetic fibers within the periosteum. In both layers, the great majority of TH+ fibers are closely associated with CD31+ blood vessels and wind around the larger vessels in a corkscrew pattern. In contrast, the majority of CGRP+ and NF200+ sensory fibers in both layers lack a clear association with CD31+ blood vessels and appear to be organized in a dense net-like meshwork to detect mechanical distortion of periosteum and bone. This organization would explain why stabilization/fixation causes a marked attenuation of movement-evoked fracture pain. Understanding the organization, plasticity and molecular characteristics of sensory and sympathetic nerve fibers innervating the skeleton may permit the development of novel mechanism-based therapies for treating non-malignant skeletal pain.

show abstract

Section: Cambium Layermentioning

confidence: 44%

Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum: Implications for the generation and maintenance of bone fracture pain

Martin

Jiménez-Andrade

Ghilardi

et al. 2007

Neuroscience Letters

101

View full text Add to dashboard Cite

show abstract

“…The presence in bone of cell processes labeled with neural tip markers such as synaptophysin has also been documented. Overall, these data provide evidence for the existence of functional nerve fibers within the bone tissue (Gronblad et al, 1984;Hohmann et al, 1986;Bjurholm et al, 1988;Serre et al, 1999). Some of these nerve fibers are in contact with cells lining the trabeculae (osteoblasts and osteoclasts), suggesting a direct control of bone cell function (Serre et al, 1999).…”

Section: Introductionmentioning

confidence: 58%

Expression of Semaphorin‐3A and its receptors in endochondral ossification: Potential role in skeletal development and innervation

Gomez

Burt‐Pichat

Malléin-Gerin

et al. 2005

Developmental Dynamics

View full text Add to dashboard Cite

Bone tissue is densely innervated, and there is increasing evidence for a neural control of bone metabolism. Semaphorin-3A is a very important regulator of neuronal targeting in the peripheral nervous system as well as in angiogenesis, and knockout of the Semaphorin-3A gene induces abnormal bone and cartilage development. We analyzed the spatial and temporal expression patterns of Semaphorin-3A signaling molecules during endochondral ossification, in parallel with the establishment of innervation. We show that osteoblasts and chondrocytes differentiated in vitro express most members of the Semaphorin-3A signaling system (Semaphorin-3A, Neuropilin-1, and Plexins-A1 and -A2). In vitro, osteoclasts express most receptor chains but not the ligand. In situ, these molecules are all expressed in the periosteum and by resting, prehypertrophic and hypertrophic chondrocytes in ossification centers before the onset of neurovascular invasion. They are detected later in osteoblasts and also osteoclasts, with differences in intensity and regional distribution. Semaphorin-3A and Neuropilin-1 are also expressed in the bone marrow. Plexin-A3 is not expressed by bone cell lineages in vitro. It is detected early in the periosteum and hypertrophic chondrocytes. After the onset of ossification, this chain is restricted to a network of cell processes in close vicinity to the cells lining the trabeculae, similar to the pattern observed for neural markers at the same stages. After birth, while the density of innervation decreases, Plexin-A3 is strongly expressed by blood vessels on the ossification front. In conclusion, Semaphorin-3A signaling is present in bone and seems to precede or coincide at the temporal but also spatial level with the invasion of bone by blood vessels and nerve fibers. Expression patterns suggest Plexin-A3/Neuropilin-1 as a candidate receptor in target cells for the regulation of bone innervation by Semaphorin-3A. Developmental Dynamics 234:393-403, 2005.

show abstract

“…The mechanism of tumor-induced bone pain is thought to be similar in mouse and human as both are mediated by excessive bone remodeling, release of algogenic inflammatory and tumor products. Previous studies have shown the presence of nerve fibers in bones of rats (52), cats (56), dogs (57), and horses (58) in addition to humans (59), and this pain mechanism could also be mediated by tumorinduced injury to nerve fibers that innervate the bone. If anti-NGF therapies can block tumor-induced bone pain, retain their analgesic efficacy with disease progression, and provide significant opioid-sparing action without significant unwanted side effects, they may provide significant advantages over the analgesics that are currently used to treat bone cancer pain.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

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. (Cancer Res 2005; 65(20): 9426-35)

show abstract

Innervation of human bone periosteum by peptidergic nerves

Cited by 94 publications

References 12 publications

Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum: Implications for the generation and maintenance of bone fracture pain

Organization of a unique net-like meshwork of CGRP+ sensory fibers in the mouse periosteum: Implications for the generation and maintenance of bone fracture pain

Expression of Semaphorin‐3A and its receptors in endochondral ossification: Potential role in skeletal development and innervation

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

Contact Info

Product

Resources

About