nach oben

Clinical Orthopaedics and Related Research®

Erschienen in:

01.12.2009 | Symposium: Tribute to Dr. Marshall Urist: Musculoskeletal Growth Factors

Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study

verfasst von: Hideki Yoshikawa, MD, PhD, Kiyoko Yoshioka, Takanobu Nakase, MD, PhD, Kazuyuki Itoh, MD, PhD

Erschienen in: Clinical Orthopaedics and Related Research® | Ausgabe 12/2009

Einloggen, um Zugang zu erhalten

Abstract

The small GTPase Rho and Rho-associated protein kinase (Rho kinase, ROCK) signal participates in a variety of biological functions including vascular contraction, tumor invasion, and penile erection. Evidence also suggests Rho-ROCK is involved in signaling for mesenchymal cellular differentiation. However, whether it is involved in osteoblastic differentiation is unknown. We therefore asked whether Rho-ROCK signaling participates in recombinant human bone morphogenetic protein (rhBMP-2)-induced osteogenesis both in vitro and in vivo. Continuous delivery of a specific ROCK inhibitor (Y-27632) enhanced ectopic bone formation induced by rhBMP-2 impregnated into an atelocollagen carrier in mice without affecting systemic bone metabolism. Treatment with Y-27632 also enhanced the osteoblastic differentiation of cultured murine neonatal calvarial cells. These effects were associated with increased expression of BMP-4 gene. Expression of a dominant negative mutant of ROCK in ST2 cells promoted osteoblastic differentiation, while a constitutively active mutant of ROCK attenuated osteoblastic differentiation and the ROCK inhibitor reversed this phenotype. Thus, ROCK inhibits osteogenesis, and a ROCK inhibitor in combination with the local delivery of rhBMP/collagen composite may be clinically applicable for stimulating bone formation.

Bishop GB, Einhorn TA. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop. 2007;6:721–727.CrossRef

Chitaley K, Wingard CJ, Webb RC, Branam H, Stopper VS, Lewis RW, Mills TM. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nature Med. 2001;7:119–122.CrossRefPubMed

Chrzanowska-Wodnicka M, Burridge K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol. 1996;133:1403–1415.CrossRefPubMed

Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK 1. Nature Cell Biol. 2001;3:339–345.CrossRefPubMed

Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa-1: a transcriptional activator of osteoblast differentiation. Cell. 1997;89:747–754.CrossRefPubMed

Higuchi C, Myoui A, Hashimoto N, Kuriyama K, Yoshioka K, Yoshikawa H, Itoh K. Continuous inhibition of MAPK signaling promotes the early osteoblastic differentiation and mineralization of extracellular matrix. J Bone Miner Res. 2002;17:1785–1794.CrossRefPubMed

Hirota S, Takaoka K, Hashimoto J, Nakase T, Takemura T, Morii E, Fukuyama A, Morihana K, Kitamura Y, Nomura S. Expression of mRNA of murine bone-related proteins in ectopic bone induced by murine bone morphogenetic protein-4. Cell Tissue Res. 1994;277:27–32.CrossRefPubMed

Hoshino M, Namikawa T, Kato M, Terai H, Taguchi S, Takaoka K. Repair of bone defects in revision hip arthroplasty by implantation of a new bone-inducing material comprised of recombinant human BMP-2, Beta-TCP powder, and a biodegradable polymer: an experimental study in dogs. J Orthop Res. 2007;25:1042–1051.CrossRefPubMed

Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 1996;15:1885–1893.PubMed

10.

Ishizaki T, Naito M, Fujisawa K, Maekawa M, Watanabe N, Saito Y, Narumiya S. p160^ROCK, a Rho-associated coiled-coil forming protein kinase, works downstream of Rho and induces focal adhesions. FEBS Lett. 1997;404:118–124.CrossRefPubMed

11.

Itoh F, Asao H, Sugamura K, Heldin CH, Dijke PT, Itoh S. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J. 2001;20:4132–4142.CrossRefPubMed

12.

Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nature Med. 1999;5:221–225.CrossRefPubMed

13.

Kaito T, Myoui A, Takaoka K, Saito N, Nishikawa M, Tamai N, Ohgushi H, Yoshikawa H. Potentiation of the activity of bone morphogenetic protein-2 in bone regeneration by a PLA-PEG/hydroxyapatite composite. Biomaterials, 2005;26:73–79.CrossRefPubMed

14.

Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–764.CrossRefPubMed

15.

Krause F, Younger A, Weber M. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. J Bone Joint Surg Am. 2008;90:1168–1169.PubMed

16.

Kretzschmar M, Doody J, Massague J. Opposing BMP and EGF signaling pathways converge on the TGF-β family mediator Smad1. Nature. 1997;389:618–622.CrossRefPubMed

17.

Kuwabara H, Wada T, Oda T, Yoshikawa H, Sawada N, Kokai Y, Ishii S. Overexpression of the granulocyte colony-stimulating factor gene impairs bone morphogenetic protein responsiveness in mice. Lab Invest. 2001;81:1133–1141.PubMed

18.

Leung T, Manser E, Tan L, Lim L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem. 1995;270:29051–29054.CrossRefPubMed

19.

Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for the small GTP binding protein Rho. EMBO J. 1996;15:2208–2216.PubMed

20.

Miyazono K, Kusanagi K, Inoue H. Divergence and convergence of TGF-beta/BMP signaling. J Cell Physiol. 2001;187:265–276.CrossRefPubMed

21.

Mizuno M, Kuboki Y. Osteoblast-related gene expression of bone marrow cells during the osteoblastic differentiation induced by type I collagen. J Biochem. 2001;129:133–138.PubMed

22.

Mori S, Yoshikawa H, Hashimoto J, Ueda T, Funai H, Kato M, Takaoka K. Antiangiogenic agent (TNP-470) inhibition of ectopic bone formation induced by bone morphogenetic protein-2. Bone. 1998;22:99–105.CrossRefPubMed

23.

Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286:1946–1949.CrossRefPubMed

24.

Murakami N, Saito N, Horiuchi H, Okada T, Nozaki K, Takaoka K. Repair of segmental defects in rabbit humeri with titanium fiber mesh cylinders containing recombinant human bone morphogenetic protein-2 (rhBMP-2) and a synthetic polymer. J Biomed Mater Res. 2002;62:169–174.CrossRefPubMed

25.

Nakase T, Nomura S, Yoshikawa H, Hashimoto J, Hirota S, Kitamura Y, Oikawa S, Ono K, Takaoka K. Transient and localized expression of bone morphogenetic protein 4 messenger RNA during fracture healing. J Bone Miner Res. 1994;9:651–659.PubMedCrossRef

26.

Ohnaka K, Shimoda S, Nawata H, Shimokawa H, Kaibuchi K, Iwamoto Y, Takayanagi R. Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts. Biochem Biophys Res Commun. 2001;287:337–342.CrossRefPubMed

27.

Reddi AH. Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotechnol. 1998;16:247–252.CrossRefPubMed

28.

Sahai E, Alberts AS, Treisman R. RhoA effector mutants reveal distinct effector pathways for cytoskeletal reorganization, SRF activation and transformation. EMBO J. 1998;17:1350–1361.CrossRefPubMed

29.

Takaoka K, Koezuka M, Nakahara H. Telopeptide-depleted bovine skin collagen as a carrier for bone morphogenetic protein. J Orthop Res. 1991;9:902–907.CrossRefPubMed

30.

Tamai N, Myoui A, Hirao M, Kaito T, Ochi T, Tanaka J, Takaoka K, Yoshikawa H. A new biotechnology for articular cartilage repair: subchondral implantation of a composite of interconnected porous hydroxyapatite, synthetic polymer (PLA-PEG), and bone morphogenetic protein-2 (rhBMP-2). Osteoarthritis Cartilage. 2005;13:405–417.CrossRefPubMed

31.

Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389:990–994.CrossRefPubMed

32.

Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–899.CrossRefPubMed

33.

Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242:1528–1534.CrossRefPubMed

34.

Yoshikawa H, Taniguchi S, Yamamura H, Mori S, Sugimoto M, Miyado K, Nakamura K, Nakao K, Katsuki M, Shibata N, Takahashi K. Mice lacking smooth muscle calponin display increased bone formation that is associated with enhancement of bone morphogenetic protein responses. Genes Cells. 1998;3:685–695.CrossRefPubMed

35.

Yoshioka K, Matsumura F, Akedo H, Itoh K. Small GTP-binding protein Rho stimulates the actomyosin system, leading to invasion of tumor cells. J Biol Chem. 1998;273:5146–5154.CrossRefPubMed

Titel: Stimulation of Ectopic Bone Formation in Response to BMP-2 by Rho Kinase Inhibitor: A Pilot Study
verfasst von: Hideki Yoshikawa, MD, PhD
Kiyoko Yoshioka
Takanobu Nakase, MD, PhD
Kazuyuki Itoh, MD, PhD
Publikationsdatum: 01.12.2009
Verlag: Springer-Verlag
Erschienen in: Clinical Orthopaedics and Related Research® / Ausgabe 12/2009
Print ISSN: 0009-921X
Elektronische ISSN: 1528-1132
DOI: https://doi.org/10.1007/s11999-009-0976-6

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen.
» Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Ein Drittel der jungen Ärztinnen und Ärzte erwägt abzuwandern

07.05.2024 Klinik aktuell Nachrichten

Extreme Arbeitsverdichtung und kaum Supervision: Dr. Andrea Martini, Sprecherin des Bündnisses Junge Ärztinnen und Ärzte (BJÄ) über den Frust des ärztlichen Nachwuchses und die Vorteile des Rucksack-Modells.

Aquatherapie bei Fibromyalgie wirksamer als Trockenübungen

03.05.2024 Fibromyalgiesyndrom Nachrichten

Bewegungs-, Dehnungs- und Entspannungsübungen im Wasser lindern die Beschwerden von Patientinnen mit Fibromyalgie besser als das Üben auf trockenem Land. Das geht aus einer spanisch-brasilianischen Vergleichsstudie hervor.

Endlich: Zi zeigt, mit welchen PVS Praxen zufrieden sind

IT für Ärzte Nachrichten

Darauf haben viele Praxen gewartet: Das Zi hat eine Liste von Praxisverwaltungssystemen veröffentlicht, die von Nutzern positiv bewertet werden. Eine gute Grundlage für wechselwillige Ärztinnen und Psychotherapeuten.

Proximale Humerusfraktur: Auch 100-Jährige operieren?

01.05.2024 DCK 2024 Kongressbericht

Mit dem demographischen Wandel versorgt auch die Chirurgie immer mehr betagte Menschen. Von Entwicklungen wie Fast-Track können auch ältere Menschen profitieren und bei proximaler Humerusfraktur können selbst manche 100-Jährige noch sicher operiert werden.

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 12/2009

The Synergistic Effect of Autograft and BMP-7 in the Treatment of Atrophic Nonunions

50 Years Ago in CORR: The Parathyroid Hormone and Bone Franklin C. McLean, MD CORR 1957;9:46–60

Levels of Expression for BMP-7 and Several BMP Antagonists May Play an Integral Role in a Fracture Nonunion: A Pilot Study

Distraction Osteogenesis Enhances Remodeling of Remote Bones of the Skeleton: A Pilot Study

Enhancement of Difficult Nonunion in Children with Osteogenic Protein-1 (OP-1): Early Experience