Expression and Synthesis of Bone Morphogenetic Proteins by Osteoclasts: A Possible Path to Anabolic Bone Remodeling

Garimella, Rama Murthy; Tague, Sarah E.; Zhang, Jianghong; Belibi, Frank; Nahar, Niru; Sun, Ben Hua; Insogna, Karl L.; Wang, Jinxi; Anderson, H. Clarke

doi:10.1369/jhc.2008.950394

Cited by 74 publications

(53 citation statements)

References 67 publications

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“…In this connection, it is interesting to note that normal osteoclasts have been shown to express significant levels of BMPs (Nishimura et al 1997;Onishi et al 1998;Dhanyamraju et al 2003;Garimella et al 2006). In the present study we also observed BMP immunolocalization in osteoclasts of GATA-1 low and WT mice (data not shown).…”

Section: Discussionsupporting

confidence: 65%

Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1^low Mice

Garimella

Kacena

Tague

et al. 2007

J Histochem Cytochem.

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The mechanism of osteosclerosis associated with myelofibrosis in megakaryocyte (MK)-related myeloproliferative disorders is largely unknown. However, growth factors released from the bone marrow cells, including from MKs, have been implicated in myelofibrosis, osteosclerosis, and angiogenesis. GATA-1 is a transcription factor required for normal MK development. GATA-1 deficiency in mice (GATA-1low) leads to increased megakaryocytic proliferation, followed by osteosclerosis and myelofibrosis. In this study we investigated the expression of bone morphogenetic proteins (BMPs) and BMP receptors and their possible role in the development of osteosclerosis in the MKs of 12-month-old GATA-1low mice by immunohistochemistry, cytomorphometry, and quantitative real-time PCR. Marrow MKs from both wild-type and GATA-1low mice showed moderate to intense staining for BMP-2, −4, and −6 and BMPR-IA and BMPR-II, whereas splenic MKs showed no BMP immunostaining. Presence of BMP protein in the bone marrow of GATA-1low mice was more than that seen in controls, owing to an increased number of MKs and osteoblasts. The osteosclerosis seen in GATA-1low mice appeared not to be due to a reduced number of functional osteoclasts because the number of tartrate-resistant acid phosphatase-positive osteoclasts was greater in GATA-1low mice than in controls. Our findings demonstrate the presence of significant amounts of BMP-2, −4, and −6 along with their receptors in bone marrow MKs of WT and GATA-1low mice. The increased levels of BMPs appear to be a result of increased numbers of MKs in GATA-1low mice and may, in part, account for the stimulation of osteoblastic activity and resulting osteosclerosis.

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Section: Discussionsupporting

confidence: 65%

Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1^low Mice

Garimella

Kacena

Tague

et al. 2007

J Histochem Cytochem.

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“…osteoclast precursors. Recently, Garimella et al (36) documented that osteoclasts express BMP2, BMP4, BMP6, and BMP7. Thus, decreased expression of a Wnt signaling antagonist coupled to increased production of Wnt10b and BMP6 by osteoclasts elevates bone formation stimuli in the regions in which osteoclasts are localized.…”

Section: Discussionmentioning

confidence: 99%

Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate

Pederson¹,

Ruan²,

Westendorf

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

474

367

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Under most conditions, resorbed bone is nearly precisely replaced in location and amount by new bone. Thus, it has long been recognized that bone loss through osteoclast-mediated bone resorption and bone replacement through osteoblast-mediated bone formation are tightly coupled processes. Abundant data conclusively demonstrate that osteoblasts direct osteoclast differentiation. Key questions remain, however, as to how osteoblasts are recruited to the resorption site and how the amount of bone produced is so precisely controlled. We hypothesized that osteoclasts play a crucial role in the promotion of bone formation. We found that osteoclast conditioned medium stimulates human mesenchymal stem (hMS) cell migration and differentiation toward the osteoblast lineage as measured by mineralized nodule formation in vitro. We identified candidate osteoclast-derived coupling factors using the Affymetrix microarray. We observed significant induction of sphingosine kinase 1 (SPHK1), which catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (S1P), in mature multinucleated osteoclasts as compared with preosteoclasts. S1P induces osteoblast precursor recruitment and promotes mature cell survival. Wnt10b and BMP6 also were significantly increased in mature osteoclasts, whereas sclerostin levels decreased during differentiation. Stimulation of hMS cell nodule formation by osteoclast conditioned media was attenuated by the Wnt antagonist Dkk1, a BMP6-neutralizing antibody, and by a S1P antagonist. BMP6 antibodies and the S1P antagonist, but not Dkk1, reduced osteoclast conditioned media-induced hMS chemokinesis. In summary, our findings indicate that osteoclasts may recruit osteoprogenitors to the site of bone remodeling through SIP and BMP6 and stimulate bone formation through increased activation of Wnt/BMP pathways.one is a dynamic tissue that continuously remodels and can undergo regeneration throughout life. This continuous remodeling occurs through a dynamic process of breakdown by osteoclasts and rebuilding by osteoblasts. Bone mass in adults is maintained by a local balance between osteoclastic bone resorption and osteoblastic activities that are mediated via various factors such as hormones, growth factors, cytokines, and matrix proteins. Under most conditions, resorbed bone is nearly precisely replaced in location and amount by new bone. Thus, it has long been recognized that bone loss through osteoclast-mediated bone resorption and bone replacement through osteoblastmediated bone formation are tightly coupled. We now have clear evidence of how osteoblasts direct osteoclast differentiation through RANK and RANKL as well as other pathways (1). Questions remain as to how osteoblasts are recruited to the site after the resorption phase and how the amount of bone produced is controlled. This has led to consideration of how osteoclasts and/or their activity could promote bone formation.Mouse models and humans in whom osteoclastogenesis is perturbed have provided important insights into the role of b...

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“…In addition, many factors involved in neovascularization are released by OCs. These include not only vascular endothelial growth factor (VEGF) but also bone morphogenetic protein 7, which promotes endothelial cell survival [22], and the epithelial growth factor-like family members, that induce endothelial cell migration and tube formation [23]. Therefore, it can be believed that OCs are implicated in the involvement of neovascularization through their paracrine.…”

Section: Introductionmentioning

confidence: 99%

LncRNA-AK131850 Sponges MiR-93-5p in Newborn and Mature Osteoclasts to Enhance the Secretion of Vascular Endothelial Growth Factor a Promoting Vasculogenesis of Endothelial Progenitor Cells

Quan

Liang

et al. 2018

Cell Physiol Biochem

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Background/Aims: In the process of bone development and remodeling, the vasculature is regarded as the communicative network between the bone and neighboring tissues. Recently, it has been reported that the processes of angiogenesis and osteogenesis are coupled temporally and spatially. However, few studies reported the relationship and relevant mechanism between osteoclastogenesis and vasculogenesis. Methods: Arraystar Mouse lncRNA microarray V3.0 was firstly used to analyze the differentially expressed lncRNA genes in osteoclast different stages during osteoclastogenesis. Cell counting kit 8 (CCK-8) analysis, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, migration and tube formation assays were used to detect impact of osteoclast different stages on the proliferation, differentiation, migration and tube formation of endothelial progenitor cells (EPCs), respectively. Finally, transfection of AK131850 shRNA, miR-93-5p mimic and miR-93-5p inhibitor, qRT-PCR, western blotting, enzyme-linked immunosorbent assay (ELISA), fluorescence in situ hybridization (FISH) and luciferase reporter assay were carried out to dissect molecular mechanisms. Results: In this study, we found that newborn OCs (N-OC) and mature OCs (M-OC) during osteoclastogenesis significantly promoted proliferation, differentiation, migration and tube formation of endothelial progenitor cells (EPCs). Through lncRNA microarray and GO&pathway analysis, we found that AK131850 and co-expressed gene, vascular endothelial growth factor a (VEGFa), were significantly up-regulated in N-OC and M-OC. After inhibition of AK131850 the promoting effect of N-OC and M-OC on EPCs was reversed. Furthermore, we found that AK131850 directly competed miR-93-5p in N-OC and M-OC through sponge, thereby increasing VEGFa transcription, expression and secretion through derepressing of miR-93-5p on VEGFa. Conclusion: Our results provided the first finding that lncRNA-AK131850 sponged miR-93-5p in N-OC and M-OC during osteoclastogenesis to enhance the secretion of VEGFa, thus promoting vasculogenesis of EPCs.

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Expression and Synthesis of Bone Morphogenetic Proteins by Osteoclasts: A Possible Path to Anabolic Bone Remodeling

Cited by 74 publications

References 67 publications

Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1^low Mice

Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1^low Mice

Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate

LncRNA-AK131850 Sponges MiR-93-5p in Newborn and Mature Osteoclasts to Enhance the Secretion of Vascular Endothelial Growth Factor a Promoting Vasculogenesis of Endothelial Progenitor Cells

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Expression and Synthesis of Bone Morphogenetic Proteins by Osteoclasts: A Possible Path to Anabolic Bone Remodeling

Cited by 74 publications

References 67 publications

Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1low Mice

Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1low Mice

Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate

LncRNA-AK131850 Sponges MiR-93-5p in Newborn and Mature Osteoclasts to Enhance the Secretion of Vascular Endothelial Growth Factor a Promoting Vasculogenesis of Endothelial Progenitor Cells

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Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1^low Mice

Expression of Bone Morphogenetic Proteins and their Receptors in the Bone Marrow Megakaryocytes of GATA-1^low Mice