Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function

Federico Furlan, Clara Galbiati, Niklas R. Jorgensen, Jens Erik B Jensen, Emanuela Mrak, Alessandro Rubinacci, Francesco Talotta, Pasquale Verde, Francesco Blasi

Research output: Contribution to journalArticle

Abstract

The uPAR and its ligand uPA are expressed by both osteoblasts and osteoclasts. Their function in bone remodeling is unknown. We report that uPAR-lacking mice display increased BMD, increased osteogenic potential of osteoblasts, decreased osteoclasts formation, and altered cytoskeletal reorganization in mature osteoclasts. Introduction: Urokinase receptor (uPAR) is actively involved in the regulation of important cell functions, such as proliferation, adhesion, and migration. It was previously shown that the major players in bone remodeling, osteoblasts and osteoclasts, express uPAR and produce urokinase (uPA). The purpose of this study was to investigate the role of uPAR in bone remodeling. Materials and Methods: In vivo studies were performed in uPAR knockout (KO) and wildtype (WT) mice on a C57Bl6/SV129 (75:25) background. Bone mass was analyzed by pQCT. Excised tibias were subjected to mechanical tests. UPAR KO calvaria osteoblasts were characterized by proliferation assays, RT-PCR for important proteins secreted during differentiation, and immunoblot for activator protein 1 (AP-1) family members. In vitro osteoclast formation was tested with uPAR KO bone marrow monocytes in the presence of macrophage-colony stimulating factor (M-CSF) and RANKL. Phalloidin staining in osteoclasts served to study actin ring and podosome formation. Results: pQCT revealed increased bone mass in uPAR-null mice. Mechanical tests showed reduced load-sustaining capability in uPAR KO tibias. uPAR KO osteoblasts showed a proliferative advantage with no difference in apoptosis, higher matrix mineralization, and earlier appearance of alkaline phosphatase (ALP). Surface RANKL expression at different stages of differentiation was not altered. AP-1 components, such as JunB and Fra-1, were upregulated in uPAR KO osteoblasts, along with other osteoblasts markers. On the resorptive side, the number of osteoclasts formed in vitro from uPAR KO monocytes was decreased. Podosome imaging in uPAR KO osteoclasts revealed a defect in actin ring formation. Conclusions: The defective proliferation and differentiation of bone cells, coincident with both aberrant expression of transcription factors and cytoskeletal organization, are typical uPAR-dependent molecular phenotypes, and we have now shown their function in osteoblasts and osteoclasts function in vivo.

Original languageEnglish
Pages (from-to)1387-1396
Number of pages10
JournalJournal of Bone and Mineral Research
Volume22
Issue number9
DOIs
Publication statusPublished - Sep 2007

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Urokinase Plasminogen Activator Receptors
Osteoclasts
Osteoblasts
Homeostasis
Bone and Bones
Bone Remodeling
Transcription Factor AP-1
Urokinase-Type Plasminogen Activator
Tibia
Actins
Monocytes
Phalloidine
Macrophage Colony-Stimulating Factor
Skull
Knockout Mice
Alkaline Phosphatase
Cell Differentiation
Transcription Factors
Bone Marrow
Apoptosis

Keywords

  • Bone remodeling
  • Osteoblast
  • Osteoclast
  • Osteoporosis
  • Urokinase receptor

ASJC Scopus subject areas

  • Surgery

Cite this

Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function. / Furlan, Federico; Galbiati, Clara; Jorgensen, Niklas R.; Jensen, Jens Erik B; Mrak, Emanuela; Rubinacci, Alessandro; Talotta, Francesco; Verde, Pasquale; Blasi, Francesco.

In: Journal of Bone and Mineral Research, Vol. 22, No. 9, 09.2007, p. 1387-1396.

Research output: Contribution to journalArticle

Furlan, F, Galbiati, C, Jorgensen, NR, Jensen, JEB, Mrak, E, Rubinacci, A, Talotta, F, Verde, P & Blasi, F 2007, 'Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function', Journal of Bone and Mineral Research, vol. 22, no. 9, pp. 1387-1396. https://doi.org/10.1359/jbmr.070516
Furlan, Federico ; Galbiati, Clara ; Jorgensen, Niklas R. ; Jensen, Jens Erik B ; Mrak, Emanuela ; Rubinacci, Alessandro ; Talotta, Francesco ; Verde, Pasquale ; Blasi, Francesco. / Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function. In: Journal of Bone and Mineral Research. 2007 ; Vol. 22, No. 9. pp. 1387-1396.
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