The effects of the endothelin family peptides on cultured osteoblastic cells from rat calvariae

doi:10.1016/0006-291X(90)90491-5

Biochemical and Biophysical Research Communications

Volume 170, Issue 3, 16 August 1990, Pages 998-1005

https://doi.org/10.1016/0006-291X(90)90491-5 Get rights and content

Abstract

The activities of three isoforms of the endothelin (ET) family peptides, ET-1, ET-2 and ET-3, were studied in cultured osteoblastic cells from neonatal rat calvariae. All three isoforms induce stimulation of DNA synthesis and reductions in cellular alkaline phosphatase activity in a dose-dependent manner with the rank order of potency: ET-1⋍ET-2>ET-3. The ¹²⁵I-labeled ET binding and affinity-cross linking experiments show the presence of a single class of the ET binding sites with a more than 10-fold higher affinity for ET-1 and ET-2 as compared to ET-3. The endothelins dose-dependently stimulate the production of inositol phosphates and induce mobilization of Ca²⁺ with the similar relative potency to that for the receptor binding. These results indicate that osteoblastic cells possess the endothelin receptor with a high affinity for ET-1 and ET-2 that is coupled to phospholipase C, and that the endothelins modulate cellular functions via this receptor.

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However, the complexities of how prostate tumor cells influence bone remodeling remain to be elucidated. ET-1 (otherwise known as preproendothelin-1, or PPET1), a peptide originally identified on the basis of its potent vasoconstrictive activity, is a common mitogenic factor for osteoblasts and is capable of inhibiting osteoclastic bone resorption [12–14]. Overexpression of ET-1 by cancer cells has been documented in various human cancers and contributes to a favorable growth microenvironment in bone by interacting with osteoblasts [15,16].
Bone metastasis is a frequent occurrence in prostate cancer (PCa) that is associated with severe complications such as fracture, bone pain and hypercalcemia. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. In our previous data, we have described how the involvement of the Wnt-induced secreted protein-1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) system in this tumor–bone interaction contributes to human PCa cell motility. In this study, we found that WISP-1 regulates bone mineralization by inducing bone morphogenetic protein-2 (BMP2), BMP4 and osteopontin (OPN) expression in osteoblasts. We also found that WISP-1 inhibited RANKL-dependent osteoclastogenesis. Moreover, osteoblast-derived WISP-1 enhanced VCAM-1 expression in PCa cells and subsequently promoted the adherence of cancer cells to osteoblasts. Furthermore, endothelin-1 (ET-1) expression in PCa cells was regulated by osteoblast-derived WISP-1, which promoted integrin α4β1 expression in osteoblasts via the MAPK pathway. Pretreatment of PCa cells with VCAM-1 antibody or osteoblasts with integrin α4β1 antibody attenuated the adherence of PCa cells to osteoblasts, suggesting that integrin α4β1 serves as a ligand that captures VCAM-1⁺ metastatic tumor cells adhering to osteoblasts. Our findings reveal that osteoblast-derived WISP-1 plays a key role in regulating the adhesion of PCa cells to osteoblasts via the VCAM-1/integrin α4β1 system. Osteoblast-derived WISP-1 is a promising target for the prevention and inhibition of PCa-bone interaction.
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Experimental procedures were conducted on cultured osteoblastic cells (MC3T3E1), fetal rat calvarial (FRC) cells, and human osteoblastic cells (HOC). Takuwa et al. [5] reported that ET-1, -2, and -3 stimulated DNA synthesis and reduced alkaline phosphatase activity in the order of ET-1 = ET-2 > ET-3 in FRC cells. Kitten et al. [11] demonstrated that ET-1 responses were regulated by osteogenic protein-1 (OP-1), and that ET-1-mediated calcium signaling and ligand binding were completely abolished by the ETAR antagonist BQ-123, which indicated that the effects of ET-1 were mediated by the receptor.
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.
We reviewed 136 manuscripts and papers, concerning about ET and ETR, how (1) ET and ETR stimulate osteoblastic activities, (2) P⁴²/P⁴⁴ MAP kinase activation is mediated in ET-1-induced IL-6 synthesis, (3) ET induces Ca²⁺ mobilization and the activation of protein kinase C, (4) ET-1 regulates phosphorylation of connexin-43, and connexin-43 is predominant in the differentiation of osteogenic cells, and (5) ET inhibited the mutual process of osteoblasts.
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ET is one of the potent mediators of bone regeneration and morphogenesis, including skeletal formation, in craniofacial development.
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Mounting evidence suggests reconceptualizing osteoarthritis (OA) as an inflammatory disorder. Trauma and obesity, the common risk factors of OA, could trigger the local or systemic inflammatory cytokines cascade. Inflammatory bone loss has been well documented; yet it remains largely unknown about the link between the inflammation and hypertrophic changes of subchondral bone seen in OA, such as osteophytosis and sclerosis. Amid a cohort of inflammatory cytokines, endothelin-1 (ET-1) could stimulate the osteoblast-mediated bone formation in both physiological (postnatal growth of trabecular bone) and pathological conditions (bone metastasis of prostate or breast cancer). Also, ET-1 is known as a mitogen and contributes to fibrosis in various organs, e.g., skin, liver, lung, kidney heart and etc., as a result of inflammatory or metabolic disorders. Subchondral bone sclerosis shared the similarity with fibrosis in terms of the overproduction of collagen type I. We postulated that ET-1 might have a hand in the subchondral bone sclerosis of OA. Meanwhile, ET-1 was also able to stimulate the production of matrix metalloproteinase (MMP)-1 and 13 by articular chondrocytes and synoviocytes, by which it might trigger the enzymatic degradation of articular cartilage. Taken together, ET-1 signaling may play a role in destruction of bone-cartilage unit in the pathogenesis of OA; it warrants further investigations to potentiate ET-1 as a novel diagnostic biomarker and therapeutic target for rescue of OA.
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Prostate cancer (PCa) is the most common cancer and the third most common cause of cancer related mortality in men in the United States. Hormonal therapy remains the most effective therapy for patients with advanced prostate cancer, inhibiting proliferation and inducing apoptosis in tumor cells. Unfortunately, after short-term remissions (18–24 months), surviving tumor cells recur with castrate resistant prostate cancer (CRPC) with inevitable progression, development of metastases mainly in bone, and death within 2–3 years in most men. Improved understanding of the molecular basis underlying bone-specific metastases and resistance to ADT or chemotherapy will facilitate the rational design of targeted therapeutics. In addition to castrate resistant disease, a second unique characteristic of PCa progression is bone-predominant metastatic progression. The bone is the most prominent site for metastases in prostate cancer. Bone metastases are associated with a significant increase of pain and serious complications. Bone provides a rich microenvironment for establishment of PCa metastases, at least in part, because of its dense reservoir of growth regulatory factors, extracellular matrix proteins, and hydroxyapatite scaffolds to support tumor growth. Over the last few years, numerous gene targets that regulate tumor-bone stromal interaction have been identified, and many novel compounds have entered clinical trials either as single agents or in combination with cytotoxic chemotherapy. Due to rapid progress of this field, it is beyond the scope of this chapter to focus on molecular and cellular mechanisms involved in prostate cancer progression and bone metastases and will discuss incidence, morbidity and possible treatment strategies in this setting.
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Citation Excerpt :
In addition, the cleaved peptides of PTHrP in the NH2-terminal region have an homology with endothelin-1 (ET-1), another factor highly secreted by these tumor cells [36]. ET-1 is a vasoconstrictor but also represents a mitogenic factor for osteoblasts [37]. It is elevated in the serum of androgen-independent prostate cancers and its secretion is enhanced by contact of the malignant cells with the bone matrix [38].
The development of a bone metastasis involves interactions between the tumor cells, the bone marrow microenvironment and the bone cells themselves. A better understanding of the pathophysiological changes occurring in bone metastasis can be obtained from histopathological examination of invaded specimens. This review focuses on the main molecular mechanisms implied in the localization and growth of malignant cells in the bone marrow. The corresponding histologic developmental stages are illustrated both in osteolytic (or mixed metastasis) or in the osteosclerotic forms by histological analysis, immunohistochemistry and microcomputed tomographic analysis of bone samples. In both cases, the malignant cells find a “fertile soil” in the bone marrow microenvironment. They use the growth factors released by bone cells for the coupling between osteoclasts/osteoblasts to promote their own development. In turn, they elaborate a variety of cytokines that can promote osteoclastogenesis (PTHrP, IL-1, IL-6…) or on the contrary, other growth factors that can boost the osteoblastic activity (ET1, IGFs). A “vicious circle” occurs between the malignant cells and the bone cells leading to the radiological expression of the metastasis.
Le développement d’une métastase osseuse implique des interactions entre les cellules malignes, le microenvironnement médullaire et les cellules osseuses elles-mêmes. L’analyse histopathologique d’échantillons osseux envahis par une métastase permet d’aborder les mécanismes physiopathologiques de la progression tumorale. La présente revue fait le point des principaux mécanismes moléculaires impliqués dans la localisation et le développement des cellules malignes dans l’os. Les stades de progression sont illustrés dans les métastases ostéolytiques (ou mixtes) et dans les formes ostésclérotiques par des clichés microscopiques en coloration standard et immunohistochimie ainsi que par microtomographie aux rayons X. Dans les deux cas, les cellules tumorales trouvent dans le microenvironnement médullaire un « sol fertile » qui va favoriser leur croissance. Elles utilisent les facteurs de croissance libérés par les cellules osseuses (et servant physiologiquement au couplage ostéoclastes/ostéoblastes) comme promoteur de leur propre expansion. En retour, elles libèrent de nombreuses cytokines qui stimulent localement l’ostéoclastogenèse (PTHrP, IL-1, IL-6…) ou, à l’inverse, d’autres facteurs qui augmentent considérablement l’activité ostéoblastique (ET-1, IGFs). Un « cercle vicieux », s’établi entre cellules malignes et cellules osseuses ; il aboutit, in fine, à l’expression radiologique de la métastase.
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Bone metastasis is very frequent in prostate cancer. Diagnosis is generally easy to make with scintigraphy and it can be confirmed by TDM and RMI. Before metastasis become symptomatic, treatment includes physical and nutritional advice with drugs to prevent bone events (pain, fracture, compression and hypercalcemia). Associated with a effective hormonal treatment, radiotherapy, surgery and analgesics are the principal treatments for symptomatic bone metastasis. Bisphosphonates play a very important role to prevent bone mass loss and to reduce bone complication events. Endothelin inhibitors belong to a new exciting concept to treat these bone metastases, data are needed in order to use them routinely.

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The effects of the endothelin family peptides on cultured osteoblastic cells from rat calvariae

Abstract

Biochem. Biophys. Res. Commun

Progress Growth Factor Res

Method Enzymol

J. Biol. Chem

FEBS letter

Eur. J. Pharmacol

Biochem. Biophys. Res. Commun

FEBS letter

Biochem. Biophys. Res. Commun