Osteoclasts are important for bone angiogenesis
ABSTRACT Increased osteoclastogenesis and angiogenesis occur in physiologic and pathologic conditions. However, it is unclear if or how these processes are linked. To test the hypothesis that osteoclasts stimulate angiogenesis, we modulated osteoclast formation in fetal mouse metatarsal explants or in adult mice and determined the effect on angiogenesis. Suppression of osteoclast formation with osteoprotegerin dose-dependently inhibited angiogenesis and osteoclastogenesis in metatarsal explants. Conversely, treatment with parathyroid hormone related protein (PTHrP) increased explant angiogenesis, which was completely blocked by osteoprotegerin. Further, treatment of mice with receptor activator of nuclear factor-kappaB ligand (RANKL) or PTHrP in vivo increased calvarial vessel density and osteoclast number. We next determined whether matrix metalloproteinase-9 (MMP-9), an angiogenic factor predominantly produced by osteoclasts in bone, was important for osteoclast-stimulated angiogenesis. The pro-angiogenic effects of PTHrP or RANKL were absent in metatarsal explants or calvaria in vivo, respectively, from Mmp9(-/-) mice, demonstrating the importance of MMP-9 for osteoclast-stimulated angiogenesis. Lack of MMP-9 decreased osteoclast numbers and abrogated angiogenesis in response to PTHrP or RANKL in explants and in vivo but did not decrease osteoclast differentiation in vitro. Thus, MMP-9 modulates osteoclast-stimulated angiogenesis primarily by affecting osteoclasts, most probably by previously reported migratory effects on osteoclasts. These results clearly demonstrate that osteoclasts stimulate angiogenesis in vivo through MMP-9.
- SourceAvailable from: Domenico Ribatti
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- "OPN knockout mice display minimal bone resorption compared with wild type and decreased osteoclast association at the bone surface (Asou et al., 2001). Secretion of matrix metalloproteinases-9 (MMP-9) by osteoclasts enhances angiogenesis through the release of VEGF from the ECM (Cackowski et al., 2010). BM ECs, in turn, secrete hepatocyte growth factor (HGF) that stimulates MMP- 9 secretion by MM plasma cells, enhancing their invasive capacity (Vande Broek et al., 2004). "
ABSTRACT: Bone marrow (BM) contains hematopoietic stem cells (HSCs) and nonhematopoietic cells. HSCs give rise to all types of mature blood cells, while the nonhematopoietic component includes osteoblasts/osteoclasts, endothelial cells (ECs), endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs). These cells form specialized "niches" which are close to the vasculature ("vascular niche") or to the endosteum ("osteoblast niche"). The "vascular niche", rich in blood vessels where ECs and mural cells (pericytes and smooth muscle cells), create a microenvironment affecting the behavior of several stem and progenitor cells. The vessel wall acts as an independent niche for the recruitment of EPCs and MSCs. This chapter will focus on the description of the role of BM niches in the control of angiogenesis occurring during multiple myeloma progression. Copyright © 2015 Elsevier Inc. All rights reserved.International review of cell and molecular biology 01/2015; 314:259-82. DOI:10.1016/bs.ircmb.2014.10.004 · 3.42 Impact Factor
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- "The assay was performed according to established procedure , . Briefly, metatarsal bones were dissected from E17.5 embryos, cultured in 24-well plates in 150 µl αMEM containing 10% fetal calf serum, L-glutamine (2 mM) and penicillin (100 U/ml)/streptomycin (100 µg/ml) for 72 hours, and then changed to 250 µl of fresh medium. "
ABSTRACT: Erythropoietin (EPO)/erythropoietin receptor (EPOR) signaling is involved in the development and regeneration of several non-hematopoietic tissues including the skeleton. EPO is identified as a downstream target of the hypoxia inducible factor-α (HIF-α) pathway. It is shown that EPO exerts a positive role in bone repair, however, the underlying cellular and molecular mechanisms remain unclear. In the present study we show that EPO and EPOR are expressed in the proliferating, pre-hypertrophic and hypertrophic zone of the developing mouse growth plates as well as in the cartilaginous callus of the healing bone. The proliferation rate of chondrocytes is increased under EPO treatment, while this effect is decreased following siRNA mediated knockdown of EPOR in chondrocytes. EPO treatment increases biosynthesis of proteoglycan, accompanied by up-regulation of chondrogenic marker genes including SOX9, SOX5, SOX6, collagen type 2, and aggrecan. The effects are inhibited by knockdown of EPOR. Blockage of the endogenous EPO in chondrocytes also impaired the chondrogenic differentiation. In addition, EPO promotes metatarsal endothelial sprouting in vitro. This coincides with the in vivo data that local delivery of EPO increases vascularity at the mid-stage of bone healing (day 14). In a mouse femoral fracture model, EPO promotes cartilaginous callus formation at days 7 and 14, and enhances bone healing at day 28 indexed by improved X-ray score and micro-CT analysis of microstructure of new bone regenerates, which results in improved biomechanical properties. Our results indicate that EPO enhances chondrogenic and angiogenic responses during bone repair. EPO's function on chondrocyte proliferation and differentiation is at least partially mediated by its receptor EPOR. EPO may serve as a therapeutic agent to facilitate skeletal regeneration.PLoS ONE 07/2014; 9(7):e102010. DOI:10.1371/journal.pone.0102010 · 3.23 Impact Factor
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- "OPN knockout mice display minimal bone resorption compared with wild type and decreased osteoclast association at the bone surface . Secretion of MMP-9 by osteoclasts enhances angiogenesis through the release of VEGF from the ECM . "
ABSTRACT: In patients with multiple myeloma (MM), the bone marrow (BM) contains hematopoietic stem cells (HSCs) and non-hematopoietic cells. HSCs are able to give rise to all types of mature blood cells, while the non hematopoietic component includes mesenchymal stem cells (MSCs), fibroblasts, osteoblasts, osteoclasts, chondroclasts, endothelial cells, endothelial progenitor cells (EPCs), B and T lymphocytes, NK cells, erythrocytes, megakaryocytes, platelets, macrophages and mast cells. All of these cells form specialized "niches" in the BM microenvironment which are close to the vasculature ("vascular niche") or to the endosteum ("osteoblast niche"). The "vascular niche" is rich in blood vessels where endothelial cells and mural cells (pericytes and smooth muscle cells) create a microenvironment that affects the behavior of several stem and progenitor cells. The vessel wall serves as an independent niche for the recruitment of endothelial progenitor cells, MSCs and HSCs. The activation by angiogenic factors and inflammatory cytokines switch the "vascular niche" to promote MM tumor growth and spread. This review will focus on the mechanisms involved in the generation of signals released by endothelial cells in the "vascular niche" that promote tumor growth and spread in MM. © 2014 Elsevier Ltd. All rights reserved.Thrombosis Research 05/2014; 133 Suppl 2(2):S102-6. DOI:10.1016/S0049-3848(14)50017-5 · 2.45 Impact Factor