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      Zoledronate suppressed angiogenesis and osteogenesis by inhibiting osteoclasts formation and secretion of PDGF-BB

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          Abstract

          Purpose

          Bisphosphonates related osteonecrosis of jaw (BRONJ) is a severe complication of systemic BPs administration, the mechanism of which is still unclarified. Recently, platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts was reported to promote angiogenesis and osteogenesis. This study aimed to clarify whether bisphosphonates suppressed preosteoclasts releasing PDGF-BB, and whether the suppression harmed coupling of angiogenesis and osteogenesis, which could contribute to BRONJ manifestation.

          Methods and results

          Zoledronate significantly inhibited osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining and PDGF-BB secretion tested by ELISA. In line with decreasing secretion of PDGF-BB by preosteoclasts exposed to zoledronate, conditioned medium (CM) from the cells significantly induced less migration of endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) compared to CM from unexposed preosteoclasts. Meanwhile, angiogenic function of EPCs and osteoblastic differentiation of MSCs also declined when culturing with CM from preosteoclasts treated by zoledronate (PZ-CM), evidenced by tube formation assay of EPCs and alkaline phosphatase activity of MSCs. Western blot assay showed that the expression of VEGF in EPCs and OCN, RUNX2 in MSCs declined when culturing with PZ-CM compared to CM from preostoeclasts without exposure of zoledronate.

          Conclusion

          Our study found that zoledronate was able to suppress preosteoclasts releasing PDGF-BB, resulting in suppression of angiogenesis and osteogenesis. Our study may partly contributed to the mechanism of BRONJ.

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          Most cited references28

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          Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone.

          Anjali P. Kusumbe, Saravana K. Ramasamy, Ralf H. Adams (2014)
          The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.
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            Bisphosphonates: the first 40 years.

            R. Russell (2011)
            The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timely after 40years to review the history of their development and their impact on clinical medicine. This special issue of BONE contains a series of review articles covering the basic science and clinical aspects of these drugs, written by some of many scientists who have participated in the advances made in this field. The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story, and is a paradigm of a successful journey from 'bench to bedside'. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate (PPi), and it was studies on the role of PPi as the body's natural 'water softener' in the control of soft tissue and skeletal mineralisation that led to the need to find inhibitors of calcification that would resist hydrolysis by alkaline phosphatase. The observation that PPi and BPs could not only retard the growth but also the dissolution of hydroxyapatite crystals prompted studies on their ability to inhibit bone resorption. Although PPi was unable to do this, BPs turned out to be remarkably effective inhibitors of bone resorption, both in vitro and in vivo experimental systems, and eventually in humans. As ever more potent BPs were synthesised and studied, it became apparent that physico-chemical effects were insufficient to explain their biological effects, and that cellular actions must be involved. Despite many attempts, it was not until the 1990s that their biochemical actions were elucidated. It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen containing bisphosphonates (such as etidronate and clodronate) can be metabolically incorporated into non-hydrolysable analogues of ATP, which interfere with ATP-dependent intracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the crystal structure elucidated for this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. Inhibition of FPPS prevents the biosynthesis of isoprenoid compounds (notably farnesol and geranylgeraniol) that are required for the post-translational prenylation of small GTP-binding proteins (which are also GTPases) such as rab, rho and rac, which are essential for intracellular signalling events within osteoclasts. The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (γδ) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. As reviewed elsewhere in this issue, bisphosphonates are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, the skeletal complications of malignancy, and osteoporosis. Several of the leading BPs have achieved 'block-buster' status with annual sales in excess of a billion dollars. As a class, BPs share properties in common. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs. Even though many of the well-established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come. Furthermore in many areas, e.g. in cancer therapy, the way they are used is not yet optimised. New 'designer' BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled. The adventure that began in Davos more than 40 years ago is not yet over. Copyright © 2011 Elsevier Inc. All rights reserved.
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              A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone.

              Heng Zhu, Zi-Kuan Guo, Xiao‐Xia Jiang … (2010)
              Unlike humans, mouse bone marrow-derived mesenchymal stem cells (MSCs) cannot be easily harvested by adherence to plastic owing to the contamination of cultures by hematopoietic cells. The design of the protocol described here is based on the phenomenon that compact bones abound in MSCs and hematopoietic cells exist in the marrow cavities and the inner interfaces of the bones. The procedure includes flushing bone marrow out of the long bones, digesting the bone chips with collagenase type II, deprivation of the released cells and culturing the digested bone fragments, out of which fibroblast-like cells migrate and grow in the defined medium. The entire technique requires 5 d before the adherent cells are readily passaged. Further identification assays confirm that these cells are MSCs. We provide an easy and reproducible method to harvest mouse MSCs that does not require depletion of hematopoietic cells by sorting or immunomagnetic techniques.
              Article 0 comments Cited 200 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Mohammed E. Elsalanty: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 8 June 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 6
                Electronic Location Identifier: e0179248
                Affiliations
                [1 ]Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory, Sun Yat-Sen University, Guangzhou, China
                [2 ]Department of Oral Implant, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory, Sun Yat-Sen University, Guangzhou, China
                Augusta University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: GQL GSZ.

                • Data curation: SYG.

                • Formal analysis: SYG GSZ KL.

                • Funding acquisition: GQL LW YJL.

                • Investigation: SYG GSZ.

                • Methodology: SYG GSZ.

                • Project administration: GQL.

                • Resources: GQL.

                • Software: SYG SEZ XML.

                • Supervision: GQL.

                • Validation: GQL.

                • Visualization: SYG GSZ.

                • Writing – original draft: SYG GSZ.

                • Writing – review & editing: GQL SYG.

                [¤]

                Current address: Department of Oral and Maxillofacial Surgery, Guanghua School of stomatology, Guangzhou, Guangdong, China

                Article
                Publisher ID: PONE-D-16-45999
                DOI: 10.1371/journal.pone.0179248
                PMC ID: 5464661
                PubMed ID: 28594896
                SO-VID: 4140e7f6-a911-4dde-8c12-1ead7886c0d2
                Copyright © © 2017 Gao et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 6 December 2016
                Date accepted : 28 May 2017
                Page count
                Figures: 6, Tables: 0, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81172566
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81372884
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81302367
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100007162, Guangdong Science and Technology Department;
                Award ID: 2013B022000038
                Award Recipient :
                National Natural Science Foundation of China (grant numbers: 81172566, 81372884, 81302367; website: http://www.nsfc.gov.cn/publish/portal1/) Guangdong Sceience and Technology Department (grant numbers: 2013B022000038 website: http://www.gdstc.gov.cn/eng/mission.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Bone
                Subject: Osteoclasts
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Bone
                Subject: Osteoclasts
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Connective Tissue
                Subject: Bone
                Subject: Osteoclasts
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Connective Tissue
                Subject: Bone
                Subject: Osteoclasts
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Connective Tissue Cells
                Subject: Osteoclasts
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Connective Tissue
                Subject: Connective Tissue Cells
                Subject: Osteoclasts
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Biological Tissue
                Subject: Connective Tissue
                Subject: Connective Tissue Cells
                Subject: Osteoclasts
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Stem Cells
                Subject: Mesenchymal Stem Cells
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Cardiovascular Physiology
                Subject: Angiogenesis
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Cardiovascular Physiology
                Subject: Angiogenesis
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Angiogenesis
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Bone Remodeling
                Subject: Ossification
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Bone Remodeling
                Subject: Ossification
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Secretion
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Secretion
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Jaw
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Head
                Subject: Jaw
                Subject: Research and Analysis Methods
                Subject: Immunologic Techniques
                Subject: Immunoassays
                Subject: Enzyme-Linked Immunoassays
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Cell Differentiation
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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