Vascular Endothelial Growth Factor Can Substitute for Macrophage Colony-Stimulating Factor in the Support of Osteoclastic Bone Resorption

We demonstrated previously that a single injection of recombinant human macrophage colony-stimulating factor (rhM-CSF) is sufficient for osteoclast recruitment and survival in osteopetrotic (op/op) mice with a deficiency in osteoclasts resulting from a mutation in M-CSF gene. In this study, we show that a single injection of recombinant human vascular endothelial growth factor (rhVEGF) can similarly induce osteoclast recruitment in op/op mice. Osteoclasts predominantly expressed VEGF receptor 1 (VEGFR-1), and activity of recombinant human placenta growth factor 1 on osteoclast recruitment was comparable to that of rhVEGF, showing that the VEGF signal is mediated through VEGFR-1. The rhM-CSF–induced osteoclasts died after injections of VEGFR-1/Fc chimeric protein, and its effect was abrogated by concomitant injections of rhM-CSF. Osteoclasts supported by rhM-CSF or endogenous VEGF showed no significant difference in the bone-resorbing activity. op/op mice undergo an age-related resolution of osteopetrosis accompanied by an increase in osteoclast number. Most of the osteoclasts disappeared after injections of anti-VEGF antibody, demonstrating that endogenously produced VEGF is responsible for the appearance of osteoclasts in the mutant mice. In addition, rhVEGF replaced rhM-CSF in the support of in vitro osteoclast differentiation. These results demonstrate that M-CSF and VEGF have overlapping functions in the support of osteoclastic bone resorption.

• Publication year

  1999

• Venue

  Journal of Experimental Medicine

• Publication date

  1999-07-19

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/JEM.190.2.293PMID 10432291PMCID 2195572
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Vascular endothelial growth factor (VEGF) and its receptors

  1999influential reference
• Granulocyte/macrophage colony-stimulating factor and interleukin-3 correct osteopetrosis in mice with osteopetrosis mutation.

  1999cited by this paper
• Genomic organization of the flt-1 gene encoding for vascular endothelial growth factor (VEGF) receptor-1 suggests an intimate evolutionary relationship between the 7-Ig and the 5-Ig tyrosine kinase receptors.

  1998cited by this paper
• Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL.

  1998cited by this paper
• Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice.

  1998cited by this paper
• Colony‐Stimulating Factor‐1 Stimulates the Fusion Process in Osteoclasts

  1998cited by this paper
• Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.

  1998cited by this paper
• Expressions of PDGF receptor alpha, c‐Kit and Flk1 genes clustering in mouse chromosome 5 define distinct subsets of nascent mesodermal cells

  1997cited by this paper
• Anabolic effects of 1,25-dihydroxyvitamin D3 on osteoblasts are enhanced by vascular endothelial growth factor produced by osteoblasts and by growth factors produced by endothelial cells.

  1997cited by this paper
• Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1.

  1996cited by this paper
• Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor.

  1996cited by this paper
• Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

  1996cited by this paper
• The Vascular Endothelial Growth Factor Receptor Flt-1 Mediates Biological Activities

  1996cited by this paper
• Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

  1996cited by this paper
• Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium

  1995cited by this paper
• Colony-stimulating factor-1 injections improve but do not cure skeletal sclerosis in osteopetrotic (op) mice.

  1995cited by this paper
• Functional hierarchy of c-kit and c-fms in intramarrow production of CFU-M.

  1995cited by this paper
• Granulocyte-macrophage colony-stimulating factor is not responsible for the correction of hematopoietic deficiencies in the maturing op/op mouse.

  1995cited by this paper
• Expression of Mac‐2 antigen in the preosteoclast and osteoclast identified in the op/op mouse injected with macrophage colony‐stimulating factor

  1994cited by this paper
• Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR.

  1994cited by this paper
• Granulocyte-macrophage colony-stimulating factor corrects macrophage deficiencies, but not osteopetrosis, in the colony-stimulating factor-1-deficient op/op mouse.

  1994cited by this paper
• Delayed hematopoietic development in osteopetrotic (op/op) mice

  1993cited by this paper
• Transient recruitment of osteoclasts and expression of their function in osteopetrotic (op/op) mice by a single injection of macrophage colony‐stimulating factor

  1993cited by this paper
• Detection of transcripts for the receptor for macrophage colony-stimulating factor, c-fms, in murine osteoclasts.

  1992cited by this paper
• Congenital osteoclast deficiency in osteopetrotic (op/op) mice is cured by injections of macrophage colony-stimulating factor

  1991cited by this paper
• Correction by CSF-1 of defects in the osteopetrotic op/op mouse suggests local, developmental, and humoral requirements for this growth factor.

  1991cited by this paper
• Role of colony‐stimulating factors in osteoclast development

  1991cited by this paper
• Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse.

  1990cited by this paper
• The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene

  1990cited by this paper
• Generation of osteoclasts from isolated hematopoietic progenitor cells.

  1989cited by this paper
• Effects of human recombinant CSF‐GM and highly purified CSF‐1 on the formation of multinucleated cells with osteoclast characteristics in long‐term bone marrow cultures

  1986cited by this paper
• Morphological evidence of reduced bone resorption in osteopetrotic (op) mice.

  1982cited by this paper
• Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation

  1982cited by this paper
• Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse.

  1976cited by this paper
• Separation of mouse spleen cells by passage through columns of sephadex G-10.

  1974cited by this paper
• Hamilton, Boyd and Mossman's human embryology;: Prenatal development of form and function

  1972cited by this paper
• The Upper Cervical Spine. Regional Anatomy, Pathology and Traumatology; a Systemic Radiological Atlas and Text-book

  1972cited by this paper
• BriefDefinitive Report Essential Role of Macrophage Colony-Stimulating Factor in the Osteoclast Differentiation Supported by

  year unknowncited by this paper

• Rapid bone formation and remodeling via vascular infiltration of a hydroxyapatite/collagen nanocomposite beneath the calvarial periosteum

  2026cites this paper
• The role of M1/M2 macrophage polarization in the pathogenesis of obesity-related kidney disease and related pathologies

  2025cites this paper
• Mapping the spatial atlas of the human bone tissue integrating spatial and single-cell transcriptomics

  2025cites this paper
• Mild antiresorptive activity of an anti-vascular endothelial growth factor A antibody and sunitinib in a rat model of bone resorption

  2025cites this paper
• From death to birth: how osteocyte death promotes osteoclast formation

  2025cites this paper
• Unraveling Obesity and Multiple Myeloma: Insights from Epidemiology and Molecular Mechanisms

  2025cites this paper
• Anti-VEGF neutralizing antibody delays osteomucosal healing by reducing collagen formation in mice

  2025cites this paper
• Progress in research on osteoporosis secondary to SARS‐CoV‐2 infection

  2025cites this paper
• Changes in the craniofacial morphology in sclerostin knockout mice.

  2025cites this paper
• Angiogenesis in Multiple Myeloma: 25 Years of Research in This Field

  2025cites this paper
• Mechanisms Underlying Medication‐Related Osteonecrosis of the Jaw

  2024cites this paper
• Functional Scaffolds for Bone Tissue Regeneration: A Comprehensive Review of Materials, Methods, and Future Directions

  2024cites this paper
• Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

  2024cites this paper
• Exploring the Role of Hormones and Cytokines in Osteoporosis Development

  2024cites this paper
• Understanding of Tempormandibular joint osteoarthritis: pathophysiology, epidemiology and diagnosis

  2023cites this paper
• Gorham-Stout disease

  2023cites this paper
• The Impacts of COVID-19 on Musculoskeletal Health

  2022cites this paper
• Hypoxia-Inducible Factors Signaling in Osteogenesis and Skeletal Repair

  2022cites this paper
• Systemic medications and implant success: Is there a link? Part three: The effects of antiresorptive and anti-angiogenic agents on the outcome of implant therapy

  2022cites this paper
• MicroRNAs as Regulators of Phagocytosis

  2022cites this paper
• Histological and Biochemical Analysis after Posterior Mandibular Displacement in Rats

  2022cites this paper
• Current concepts from diagnosis to management in Gorham–Stout disease: a systematic narrative review of about 350 cases

  2022cites this paper
• Normalization of the Immunological Microenvironment and Sustained Minimal Residual Disease Negativity: Do We Need Both for Long-Term Control of Multiple Myeloma?

  2022cites this paper
• TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors

  2021cites this paper
• Altered temperature affect body condition and endochondral ossification in Bufo gargarizans tadpoles.

  2021cites this paper
• THE USE OF MICRO-OSTEOPERFORATION CONCEPT FOR ACCELERATING DIFFERENTIAL TOOTH MOVEMENT

  2021cites this paper
• Role of Macrophages and Related Cytokines in Kidney Disease

  2021cites this paper
• Skeletal regeneration for segmental bone loss: vascularised grafts, analogues and surrogates.

  2021cites this paper
• Functional identification of a rare vascular endothelial growth factor a (VEGFA) variant associating with the nonsyndromic cleft lip with/without cleft palate

  2021influential citation
• Cross talk between the endothelium and bone: vascular endothelial cells in bone development

  2021cites this paper
• Inhibitory Effects of Combined Bone Morphogenetic Protein 2, Vascular Endothelial Growth Factor, and Basic Fibroblast Growth Factor on Osteoclast Differentiation and Activity

  2021cites this paper
• Sequential growth factor releasing double cryogel system for enhanced bone regeneration.

  2020cites this paper
• The Extra Domain A of fibronectin facilitates osteoclastogenesis in radicular cysts through Vascular Endothelial Growth Factor.

  2020cites this paper
• Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption

  2020cites this paper
• Effects of VEGF on Prefabricated Vascularized Bone Allografts in Rats

  2020cites this paper
• Effect of continuous compressive force on the expression of RANKL, OPG, and VEGF in osteocytes.

  2020cites this paper
• CO-CULTURE SYSTEMS OF OSTEOBLASTS AND OSTEOCLASTS: SIMULATING IN VITRO BONE REMODELING IN REGENERATIVE APPROACHES.

  2020cites this paper
• Vascular endothelial growth factor and bone–vascular interactions

  2020cites this paper
• Role of the Bone Marrow Milieu in Multiple Myeloma Progression and Therapeutic Resistance.

  2020cites this paper
• Interdisciplinary Approach to the Temporomandibular Joint Osteoarthritis—Review of the Literature

  2020cites this paper
• Zoledronate Inhibits Osteoclast Differentiation via Suppressing Vascular Endothelial Growth Factor Receptor 2 Expression

  2020cites this paper
• Phenotypic impacts of CSF1R deficiencies in humans and model organisms

  2019cites this paper
• Collagen XIII-derived ectodomain regulates bone angiogenesis and intracortical remodeling.

  2019cites this paper
• Bone biology in postnatal Wistar rats following hypoxia-reoxygenation.

  2019cites this paper
• What Are the Peripheral Blood Determinants for Increased Osteoclast Formation in the Various Inflammatory Diseases Associated With Bone Loss?

  2019cites this paper
• Noninvasive Localized Cold Therapy: A New Mode of Bone Repair Enhancement

  2019cites this paper
• Autophagy and Macrophage Functions: Inflammatory Response and Phagocytosis

  2019cites this paper
• The role of physical forces in osteoclastogenesis

  2019cites this paper
• Diagnostic and therapeutic approaches in oral cavity granulomas based on new data concerning their origin and pathogenesis.

  2018cites this paper
• Bevacizumab or fibronectin gene editing inhibits the osteoclastogenic effects of fibroblasts derived from human radicular cysts

  2018cites this paper
• Influence Of Genetic Polymorphisms In Genes Of Bone Remodeling And Angiogenesis Process In The Apical Periodontitis.

  2018cites this paper
• Multiple myeloma.

  2018cites this paper
• Effect of continuous compressive force on the expression of RANKL, OPG, and VEGF in MC3T3-E1 and MLO-Y4 cells

  2018cites this paper
• Modulation of parathyroid hormone 1 receptor signaling by extracellular nucleotides

  2018cites this paper
• The origins and homeostasis of monocytes and tissue‐resident macrophages in physiological situation

  2018cites this paper
• Immunohistochemical evaluation of VEGF and tryptase for angiogenesis and mast cell counting in giant cell granulomas of the jaws

  2018cites this paper
• Breast cancer bone metastases: pathogenesis and therapeutic targets.

  2018cites this paper
• Endochondral ossification in hindlimbs during bufo gargarizans metamorphosis: A model of studying skeletal development in vertebrates

  2018cites this paper
• Transdifferentiation of adipocytes to osteoblasts: potential for orthopaedic treatment

  2018cites this paper
• EFFECT OF NICOTINE ON PERIODONTAL LIGAMENT DERIVED CELLS CULTURED UNDER MECHANICAL STRESS

  2017cites this paper
• Entstehung, Entwicklung und Migration von Makrophagen aus dem embryonalen Dottersack in vivo

  2017influential citation
• Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma

  2017cites this paper
• [Inflammation and osteoclasts].

  2017cites this paper
• Regulation of Embryonic and Postnatal Development by the CSF-1 Receptor.

  2017influential citation
• Bone Toxicology

  2017cites this paper
• A central role for reactive oxygen species (ROS) in the pathogenesis of temporomandibular joint disorders: All roads lead to ROS

  2017cites this paper
• Bone and the Immune System

  2017cites this paper
• Vascular endothelial growth factor‐transfected adipose‐derived stromal cells enhance bone regeneration and neovascularization from bone marrow stromal cells

  2017cites this paper
• Physiological roles of macrophages

  2017cites this paper
• Chapter 2 Polarized Activation of Macrophages

  2017cites this paper
• Inflammatory and Anti-Inflammatory Equilibrium, Proliferative and Antiproliferative Balance: The Role of Cytokines in Multiple Myeloma

  2017cites this paper
• The skeletal vascular system - Breathing life into bone tissue.

  2017cites this paper
• Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate

  2017cites this paper
• Monocytes and Macrophages

  2017cites this paper
• It Takes Two to Tango: Coupling of Angiogenesis and Osteogenesis for Bone Regeneration

  2017cites this paper
• Targeting the Bone Marrow Microenvironment.

  2016cites this paper
• Histological expression of vascular endothelial growth factor with neovascularization during occlusal hypofunction: animal experimental study.

  2016cites this paper
• A Comparative Study of Cathepsin D Expression in Peripheral and Central Giant Cell Granuloma of the Jaws by Immunohistochemistry Technique

  2016cites this paper
• Nanoscale bioactive glass activates osteoclastic differentiation of RAW 264.7 cells.

  2016cites this paper
• The roles of vascular endothelial growth factor in bone repair and regeneration.

  2016cites this paper
• Compression and hypoxia play independent roles while having combinative effects in the osteoclastogenesis induced by periodontal ligament cells.

  2016cites this paper
• Association of Acroosteolysis With Enhanced Osteoclastogenesis and Higher Blood Levels of Vascular Endothelial Growth Factor in Systemic Sclerosis

  2016cites this paper
• Human endothelial and foetal femur-derived stem cell co-cultures modulate osteogenesis and angiogenesis

  2016cites this paper
• Osteoclasts—Key Players in Skeletal Health and Disease

  2016cites this paper
• Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair.

  2016cites this paper
• The Role of Chondrocytes in Fracture Healing

  2016cites this paper
• The Journal of Clinical Investigation

  2016cites this paper
• Role of the colony-stimulating factor (CSF)/CSF-1 receptor axis in cancer.

  2016cites this paper
• VEGF Expression in Diabetic Rats Promotes Alveolar Bone Resorption by Porphyromonas gingivalis LPS

  2016cites this paper
• Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain

  2016cites this paper
• The Effect of Vascular Endothelial Growth Factor on Osteoclastogenesis in Rheumatoid Arthritis

  2015cites this paper
• Alternative pathways of osteoclastogenesis in inflammatory arthritis

  2015cites this paper
• Rôle de Tif1gamma dans les différenciations granulo-monocytaire et macrophagique

  2015influential citation
• VEGF-VEGFR System as a Target for Suppressing Inflammation and other Diseases.

  2015cites this paper
• Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits

  2015cites this paper
• Genetic Influences on Orthodontic Tooth Movement

  2015cites this paper
• Tissue engineering and regenerative medicine: evolving applications towards cleft lip and palate surgery

  2015cites this paper
• Raloxifene modulates regulators of osteoclastogenesis and angiogenesis in an oestrogen deficiency periapical lesion model.

  2015cites this paper
• Anti-VEGFs hinder bone healing and implant osseointegration in rat tibiae.

  2015cites this paper
• Hypoxic regulation of osteoclast differentiation and bone resorption activity

  2015cites this paper