Microisolated Mouse Osteoclasts Express VIP-1 and PACAP Receptors

doi:10.1006/bbrc.2000.3151

Biochemical and Biophysical Research Communications

Volume 274, Issue 2, 2 August 2000, Pages 400-404

https://doi.org/10.1006/bbrc.2000.3151 Get rights and content

Abstract

Skeletal tissue contains a network of nerve fibers expressing several neuropeptides, including vasoactive intestinal peptide (VIP) and the related peptide pituitary adenylate cyclase activating peptide (PACAP). These peptides have been demonstrated to regulate osteoclast formation and osteoclast activity. Using atomic force microscopy and by analysing changes of the intracellular calcium concentrations, we have recently demonstrated that multinucleated rat osteoclasts have cell membrane binding sites recognising VIP and PACAP. In the present study, we have further studied the expression of VIP receptor subtypes in mouse bone marrow cultures and isolated osteoclasts. A micromanipulation technique was used to isolate pure populations of osteoclasts formed in PTH-stimulated mouse bone marrow cultures. By reverse transcriptase polymerase chain reaction (RT-PCR), we studied the expression of mRNA for VIP-1, VIP-2, and PACAP receptors. The purity of the microisolated osteoclasts was determined by studying the expression of specific mRNA associated with the phenotypic trait of osteoclasts or osteoblasts/stromal cells. In this study, we show that mouse osteoclasts express VIP-1 and PACAP, but not VIP-2, receptor mRNA.

References (25)

A. Bjurholm et al.
J Auton. Nerv. Syst.
(1988)
M. Ahmed et al.
Regul. Pept.
(1994)
H. Mukohyama et al.
Biochem. Biophys. Res. Commun.
(2000)
D.E. Myers et al.
FEBS Lett.
(1999)
S.C. Marks et al.
Lerner, U. H.in Principles of Bone Biology (Bilezikian, J. P., Raisz, L. G., and Rodan, G. A., Eds.), pp. 581–596,...
Y.T. Konttinen et al.
Acta Orthop. Scand.
(1996)
Lundberg, P. 2000, The Neuropeptide VIP as a Regulator of Bone Cell Functions, Thesis, Umeå...
E.L. Hohmann et al.
Science
(1986)
E.L. Hill et al.
Cell Tissue Res.
(1991)

Bjurholm, A. 1988, Neuroendocrine peptides in bone, Thesis, University of Stockholm and Umeå,...

E.L. Hohmann et al.

Endocrinology

(1983)

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Multiple factors regulate the regeneration of craniofacial bone defects. The nervous system is recognized as one of the critical regulators of bone mass, thereby suggesting a role for neuronal pathways in bone regeneration. However, in the context of craniofacial bone regeneration, little is known about the interplay between the nervous system and craniofacial bone. Sensory and sympathetic nerves interact with the bone through their neuropeptides, neurotransmitters, proteins, peptides, and amino acid derivates. The neuron-derived factors, such as semaphorin 3A (SEMA3A), substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP), possess a remarkable role in craniofacial regeneration. This review summarizes the roles of these factors and recently published factors such as secretoneurin (SN) and spexin (SPX) in the osteoblast and osteoclast differentiation, bone metabolism, growth, remodeling and discusses the novel application of nerve-based craniofacial bone regeneration. Moreover, the review will facilitate understanding the mechanism of action and provide potential treatment direction for the craniofacial bone defect.
Role of vasoactive intestinal peptide in the progression of osteoarthritis through bone sclerosis and angiogenesis in subchondral bone
2020, Journal of Orthopaedic Science
Citation Excerpt :
Activation of these pathways stimulates the biosynthesis of osteoblastic alkaline phosphatase [10] and assists in decreasing osteoclast formation and activity via regulation of the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ligand pathway [4,11]. Therefore, with osteoclast expressed VPAC-1 receptors, VIP induces construction and ceased motility of osteoclasts, and decreases the osteoclast genesis [26]. VIP is intensely expressed in the subchondral bone, especially osteoblasts in early phase of DMM mice, and VIP receptor antagonist might block the VIP signaling in osteoblasts, subsequently prevent the subchondral bone sclerosis.
Osteoarthritis (OA) is a progressive joint disorder, with abnormal remodeling of subchondral bone linked to the disruption of cartilage metabolism. Nerves also play an important role in bone remodeling in OA progression, and vasoactive intestinal peptide (VIP), one of the neuropeptides, plays an important role in bone metabolism. The aim of this study was to analyze the expression pattern of VIP in subchondral bone, and its potential as a therapeutic target for OA progression.
The pattern of VIP expression in the human tibia was histologically evaluated. The effect of VIP on angiogenesis was investigated using human umbilical vein endothelial cells (HUVECs). Knee OA was induced by the resection of the medial meniscotibial ligament in C57BL/6 mice. A VIP receptor antagonist was intraperitoneally administered postoperatively, and therapeutic effects were analyzed at 4 and 8 weeks.
VIP expression in the subchondral bone increased as OA progressed in human tibia. VIP was also expressed in the vascular channels into the cartilage layer. The total length and branch points were significantly increased, due to the VIP receptor agonist in HUVECs. In OA mice, the VIP receptor antagonist could prevent cartilage degeneration and subchondral bone sclerosis. The Osteoarthritis Research Society International score in the VIP receptor antagonist group was significantly lower than in the control group.
VIP is involved in the progression of OA through its effect on subchondral bone sclerosis and angiogenesis. Inhibition of VIP signaling has the potential to be a therapeutic target to prevent OA progression.
No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing
2020, Bone
Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain.
Postmenopausal osteoporosis is associated with the regulation of SP, CGRP, VIP, and NPY
2018, Biomedicine and Pharmacotherapy
Citation Excerpt :
VIP can also directly affect bone cells. For osteoblastic activity, VIP stimulates ALP and increases calcium accumulation in bone nodules [39,40]; for osteoclastic activity, VIP inhibits osteoclast formation [41,42]. The present study showed that ovariectomy did not make a difference in terms of brain VIP and its receptors, but suppressed VIP and VPAC2 in bone, which impaired the skeleton, thus indicating that ovariectomy affected bone metabolism through local VIP signals (Table 4).
Estrogen deficiency is the main factor underlying postmenopausal osteoporosis. A large number of neuropeptides, which regulate skeletal metabolism, potentially represent a regulatory pathway for the pathogenesis of osteoporosis. The aim of this study was to explore factors involved in the regulation of bone-related neuropeptides and their association with estrogen deficiency and bone metabolism. Thirty adult female Sprague-Dawley (SD) rats were randomly divided into a control group with sham surgery (n = 15) and an ovariectomy group with bilateral oophorectomy (n = 15). After 16 weeks, serum estrogen was reduced,CTX-1 was increased and P1NP was not significantly affected in the ovariectomy group and a model of osteoporosis was established. We then investigate the gene expression and protein levels of a range of neuropeptides and their receptors, including substance P (SP) and tachykinin receptor 1 (TACR1), calcitonin gene-related peptide (CGRP) and calcitonin receptor-like (CALCRL), vasoactive intestinal polypeptide (VIP) and receptor 1 and 2 (VPAC1, 2), neuropeptide Y (NPY) and receptor Y1 and Y2, in the brain and femora. Ovariectomy reduced TACR1, CGRP, CALCRL, NPY, NPY Y2 in the brain, but increased TACR1 and decreased SP, CALCRL, VIP, VPAC2 in the bone. Collectively, our data revealed that the pathogenesis of postmenopausal osteoporosis is associated with the regulation of SP, CGRP, VIP, and NPY. These novel results are of significant importance in the development of neuropeptides as therapeutic targets.
Boning up on DPP4, DPP4 substrates, and DPP4-adipokine interactions: Logical reasoning and known facts about bone related effects of DPP4 inhibitors
2016, Bone
Citation Excerpt :
VIP binds on VIP receptor types 1 and 2 (VPAC1 and VPAC2), PACAP binds the VIP receptors and an additional PAC1 receptor, and SP binds the neurokinin 1 receptor (NK-1R). Osteoblasts express the receptors VPAC1, VPAC2 and NK-1R [95,103] whereas osteoclasts present VPAC1, PAC1 and NK-1R on their surface [145]. Neuropeptides VIP and SP exert their paracrine effects in close relation with leptin stimulation of hypothalamic nuclei mediated by the sympathetic nervous system and inhibitory and adrenergic receptors on osteoblasts [103].
Dipeptidyl peptidase 4 (DPP4) is a conserved exopeptidase with an important function in protein regulation. The activity of DPP4, an enzyme which can either be anchored to the plasma membrane or circulate free in the extracellular compartment, affects the glucose metabolism, cellular signaling, migration and differentiation, oxidative stress and the immune system. DPP4 is also expressed on the surface of osteoblasts, osteoclasts and osteocytes, and was found to play a role in collagen metabolism. Many substrates of DPP4 have an established role in bone metabolism, among which are incretins, gastrointestinal peptides and neuropeptides. In general, their effects favor bone formation, but some effects are complex and have not been completely elucidated. DPP4 and some of its substrates are known to interact with adipokines, playing an essential role in the energy metabolism. The prolongation of the half-life of incretins through DPP4 inhibition led to the development of these inhibitors to improve glucose tolerance in diabetes. Current literature indicates that the inhibition of DPP4 activity might also result in a beneficial effect on the bone metabolism, but the long-term effect of DPP4 inhibition on fracture outcome has not been entirely established. Diabetic as well as postmenopausal osteoporosis is associated with an increased activity of DPP4, as well as a shift in the expression levels of DPP4 substrates, their receptors, and adipokines. The interactions between these factors and their relationship in bone metabolism are therefore an interesting field of study.
Different sympathetic pathways control the metabolism of distinct bone envelopes
2012, Bone
Bone remodeling, the mechanism that modulates bone mass adaptation, is controlled by the sympathetic nervous system through the catecholaminergic pathway. However, resorption in the mandible periosteum envelope is associated with cholinergic Vasoactive Intestinal Peptide (VIP)-positive nerve fibers sensitive to sympathetic neurotoxics, suggesting that different sympathetic pathways may control distinct bone envelopes. In this study, we assessed the role of distinct sympathetic pathways on rat femur and mandible envelopes. To this goal, adult male Wistar rats were chemically sympathectomized or treated with agonists/antagonists of the catecholaminergic and cholinergic pathways; femora and mandibles were sampled. Histomorphometric analysis showed that sympathectomy decreased the number of preosteoclasts and RANKL-expressing osteoblasts in mandible periosteum but had no effect on femur trabecular bone. In contrast, pharmacological stimulation or repression of the catecholaminergic cell receptors impacted the femur trabecular bone and mandible endosteal retromolar zone. VIP treatment of sympathectomized rats rescued the disturbances of the mandible periosteum and alveolar wall whereas the cholinergic pathway had no effect on the catecholaminergic-dependent envelopes. We also found that VIP receptor-1 was weakly expressed in periosteal osteoblasts in the mandible and was increased by VIP treatment, whereas osteoblasts of the retromolar envelope that was innervated only by tyrosine hydroxylase-immunoreactive fibers, constitutively expressed beta-2 adrenergic receptors. These data highlight the complexity of the sympathetic control of bone metabolism. Both the embryological origin of the bone (endochondral for the femur, membranous for the mandibular periosteum and the socket wall) and environmental factors specific to the innervated envelope may influence the phenotype of the sympathetic innervation. We suggest that an origin-dependent imprint of bone cells through osteoblast–nerve interactions determines the type of autonomous system innervating a particular bone envelope.

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¹: To whom correspondence should be addressed at Department of Oral Cell Biology, Umeå University, S-901 87 Umeå, Sweden. Fax: +46-90-139289. E-mail: [email protected].

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Regular ArticleMicroisolated Mouse Osteoclasts Express VIP-1 and PACAP Receptors

Abstract

J Auton. Nerv. Syst.

Regul. Pept.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Acta Orthop. Scand.

Science

Cell Tissue Res.

Endocrinology

Regular Article
Microisolated Mouse Osteoclasts Express VIP-1 and PACAP Receptors