Role of the endothelial cell in osteoclast control: New perspectives

doi:10.1016/8756-3282(93)90234-2

Bone

Volume 14, Issue 2, March–April 1993, Pages 97-102

https://doi.org/10.1016/8756-3282(93)90234-2 Get rights and content

Abstract

The osteoclast is of central importance in the process of bone remodeling. Its function is regulated by hormones and locally produced factors. Endothelial cells occur in close proximity to the osteoclast. Some endothelial cell-derived products, including endothelins, nitric oxide, and reactive oxygen species, have been recently implicated as modulators of osteoclast function. Endothelins inhibit bone resorption and osteoclast margin ruffling (quiescence or Q effect) at concentrations similar to those effective for their primary vasoconstrictive action. Contrary to expectations, however, it has been shown that endothelin action on the osteoclast is not mediated through an elevation of cytosolic Ca²⁺. Nitric oxide (NO) produces marked cell retraction (retraction or R effect), but its detailed mode of action is unknown. However, it is clear that the effects of this autocoid are not due to enhanced cyclic guanosine monophosphate (cGMP) production, a transduction system commonly used by NO. Finally, the reactive oxygen species H₂O₂ has been shown recently to enhance osteoclastic activity. Thus, the reported effects of the endothelial cell-derived products on the osteoclast are generally consistent with a regulatory role for endothelial cells in osteoclast control and suggest the existence of unique activation pathways, well worth exploring further. Unravelling the responsible mechanisms may also help understand the pathophysiology of a range of bone and joint diseases. For example, in rheumatoid arthritis, there is increased H₂O₂ production from activated neutrophils, and bone resorption is a major pathophysiological feature.

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Adrenomedullin (ADM), a member of the calcitonin family of peptides, is a potent vasodilator and was shown to have the ability to modulate bone metabolism. We have previously found a unique cell surface antigen (Kat1 antigen) expressed in rat osteoclasts, which is involved in the functional regulation of the calcitonin receptor (CTR). Cross-linking of cell surface Kat1 antigen with anti-Kat1 antigen monoclonal antibody (mAbKat1) stimulated osteoclast formation only under conditions suppressed by calcitonin. Here, we found that ADM provoked a significant stimulation in osteoclastogenesis only in the presence of calcitonin; a similar biological effect was seen with mAbKat1 in the bone marrow culture system. This stimulatory effect on osteoclastogenesis mediated by ADM was abolished by the addition of mAbKat1. ¹²⁵I-labeled rat ADM (¹²⁵I-ADM)-binding experiments involving micro-autoradiographic studies demonstrated that mononuclear precursors of osteoclasts abundantly expressed ADM receptors, and the specific binding of ¹²⁵I-ADM was markedly inhibited by the addition of mAbKat1, suggesting a close relationship between the Kat1 antigen and the functional ADM receptors expressed on cells in the osteoclast lineage. ADM receptors were also detected in the osteoclast progenitor cells in the late mitotic phase, in which only one daughter cell of the dividing cell express ADM receptors, suggesting the semiconservative cell division of the osteoclast progenitors in the initiation of osteoclastogenesis. Messenger RNAs for the receptor activity-modifying-protein 1 (RAMP1) and calcitonin receptor-like receptor (CRLR) were expressed in cells in the osteoclast lineage; however, the expression of RAMP2 or RAMP3 was not detected in these cells. It is suggested that the Kat1 antigen is involved in the functional ADM receptor distinct from the general ADM receptor, consisting of CRLR and RAMP2 or RAMP3. Modulation of osteoclastogenesis through functional ADM receptors abundantly expressed on mononuclear osteoclast precursors is supposed to be important in the fine regulation of osteoclast differentiation in a specific osteotrophic hormonal condition with a high level of calcitonin in blood.
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It has been suggested that ET-1 is tightly bound to the plasma membrane receptor (ETR), and internalization within the lysosomes results in the downregulation of ETR. ETs inhibit bone resorption and osteoblast margin ruffling (quiescence or the Q effect) at concentrations similar to those effective for their primary vasoconstrictive action [90] (Figs. 8 and 9). Nitric oxide (NO) produces marked cell retraction (retraction or the R effect), and the reactive oxygen species H2O2 has been shown to enhance osteoclastic activity [91].
The present review describes endothelins (ETs) and endothelin receptors (ETRs) involved in the remodeling of mesenchymal tissue and bone formation, as processes of wound healing and skeletal tissue remodeling.
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Since the discovery of ETs and ETRs, the vascular physiology and biological mechanism of ETs and ETRs have been highlighted and have indicated that ET-1 mediates the proliferation and differentiation of osteoblastic (progenitor) cells. ET-1 binds to ET_AR and osteoblasts, osteoclasts, and chondrocytes reactive to ET-1 mRNA, and ET-1 production by these cells are enhanced by BMP-7. ET exhibits a mitogenic function in connective and bone tissues. ET recognizes angiogenesis with VEGF, and cooperative ET may play a role in osteogenesis via matrix formation. Metastatic tumor cells produce ET-1, which stimulates new bone formation; this finding involves osteoblastic tumor metastases, a process that inhibits ET_AR antagonists. Understanding the multiple biophysiological functions of the ET axis is beneficial for application of new treatment employing tissue regeneration.
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The present study reviewed endothelin (ET) as an endothelial vasoconstrictor of three types: ET1, ET2 and ET3 and two receptors (ET_AR, ET_BR). They were involved in bone remodeling, developmental anomalies in the mandibulo-facial area and bone metastasis from cancer of distal organs.
The tissue remodeling process has been recognized to have multiple growth factors including endothelins (ETs) and receptors (ETRs). Among ETs, ET-1 is the most potent vasoconstrictor, and it binds to ET_AR or ET_BR. The biophysiological roles of ETs and ETRs are involved not only in vascular tissues but also bone tissue. Promotion of bone formation through ET-1 will take place following dental implant, tooth extraction, destruction osteogenesis and surgical bone loss. ETs and ETRs mediate the normal development of craniovascular structure which eventually migrate to the pharyngeal arch. The CATCH 22 syndrome (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia associated with chromosome 22 microdeletion) displayed developmental malformation (3rd and 4th arch). Treacher Collins syndrome, and Pierre Robin sequence and DiGeorge/Velocardic facial syndrome are resemble this CATCH 22 syndrome.
ETs and ETRs related to biological processes in bone remodeling have been beneficial in fracture healing, bone remodeling, orthodontic tooth movement, distraction osteogenesis, surgical or traumatic bone defects and bone metastasis. ETs and ETRs influenced the embryonal development of pharyngeal arch and congenital anomalies like the CATCH 22 syndrome.
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In this study we have developed Ca₃ZrSi₂O₉ (Baghdadite) ceramics by incorporating Zirconium in Ca–Si system and determined their biological properties. Ca₃ZrSi₂O₉ ceramics possess apatite-formation ability in simulated body fluid, indicating their potential bioactivity. The response of human osteoblast like cells (HOB), osteoclast and endothelial cells when cultured on Ca₃ZrSi₂O₉ ceramics was investigated. Scanning electron microscopy and immunofluorescence studies demonstrated that this material supports HOB cell attachment with organized cytoskeleton structure. Compared to CaSiO₃, Ca₃ZrSi₂O₉ ceramics induced increased HOB proliferation and differentiation as shown by increased methyltetrazidium salt (MTS), alkaline phosphatase activity, and mRNA expression levels of bone-related genes (Collagen type I, alkaline phosphatase, Bone Sialoprotein, receptor activator of NF-κB ligand and osteoprotegerin). Ca₃ZrSi₂O₉ ceramics supported the fusion of monocytes to form functional osteoclasts with their characteristic features of f-actin ring structures and the expression of α_vβ₃ integrin consistent with functional activity. Osteoclasts cultured on Ca₃ZrSi₂O₉ expressed increased levels of osteoclast-related genes; Cathepsin K, Carbonic Anhydrase II, Matrix metalloproteinase-9, receptor activator of NF-κB and Calcitonin Receptor, consistent with the formation of functional osteoclasts. In addition to HOB and osteoclasts, Ca₃ZrSi₂O₉ supported the attachment of endothelial cells, which expressed the endothelial cell markers; ZO-1 and VE-Cadherin. Results presented here indicate that Ca₃ZrSi₂O₉ ceramics have the potential for applications in bone tissue regeneration.
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Citation Excerpt :
The 4.0% M. rubra solution showed significantly better results than other M. rubra solutions and its solvent PBS at all times. Oxygen radicals and oxygen tension have been reported to modulate osteoblast and osteoclast activities.23,24 Buttke and Trope25 stated that low levels of H2O2 in media used for storing avulsed teeth might adversely affect cells of the attachment apparatus.
The purpose of this study was to determine the ability of the juice of Morus rubra fruit to serve as a temporary storage medium for the maintenance of periodontal ligament (PDL) cell viability of avulsed teeth.
PDL cells were obtained from healthy third molars and cultured in Dulbecco’s Modified Eagle’s Medium (DMEM). Cultures were subjected to 4.0%, 2.5%, 1.5%, and 0.5% of the juice of M. rubra fruit, Hank’s balanced salt solution (HBSS), phosphate-buffered saline (PBS), and tap water. Tissue culture plates were incubated with experimental media at 37°C for 1, 3, 6, 12, or 24 hours. PDL cell viability was assessed by trypan blue exclusion. Statistical analysis of the data was accomplished using 1-way analysis of variance complemented by the Tukey test. The level of significance was 5% (P < .05).
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Original articleRole of the endothelial cell in osteoclast control: New perspectives

Abstract

Lancet

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Lancet

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Atherosclerosis

Biochem. Biophys. Res. Commun.

Bone

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Lancet

Exp. Cell Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Free Rad. Biol. Med.

Biochem. Biophys. Res. Commun.

Endothelin inhibits osteoclastic bone resorption by a direct effect on cell motility: implications for the vascular control of bone resorption

Endocrinol.

Xanthine oxido-reductase is present in human synovium

Ann. Rheum. Dis.

Cloning and expression of a cDNA encoding an endothelin receptor

Nature

Free radical involvement in the formation of lipopigments

A comparative study of disaggregated chick and rat osteoclasts in vitro: Effects of calcitonin and prostaglandins

Endocrinol.

Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide

Free radicals in biological systems—A review oriented to inflammatory processes

Brit. Med. Bull.

Activation of a cystolic ADP-ribosyltransferase by nitric oxide-generating agents

J. Biol. Chem.

Cell proliferation and oxidative stress

Free Rad. Res. Commun.

Regulation of osteoclast function

Oxygen-derived free radicals to stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo

J. Clin. Invest.

Original article
Role of the endothelial cell in osteoclast control: New perspectives