Rho kinase inhibitors stimulate the migration of human cultured osteoblastic cells by regulating actomyosin activity

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Abstract

We investigated the effects of Rho-associated kinase (ROCK) on migration and cytoskeletal organization in primary human osteoblasts and Saos-2 human osteosarcoma cells. Both cell types were exposed to two different ROCK inhibitors, Y-27632 and HA-1077. In the improved motility assay used in the present study, Y-27632 and HA-1077 significantly increased the migration of both osteoblasts and osteosarcoma cells on plastic in a dose-dependent and reversible manner. Fluorescent images showed that cells of both types cultured with Y-27632 or HA-1077 exhibited a stellate appearance, with poor assembly of stress fibers and focal contacts. Western blotting showed that ROCK inhibitors reduced myosin light chain (MLC) phosphorylation within 5 min without affecting overall myosin light-chain protein levels. Inhibition of ROCK activity is thought to enhance the migration of human osteoblasts through reorganization of the actin cytoskeleton and regulation of myosin activity. ROCK inhibitors may be potentially useful as anabolic agents to enhance the biocompatibility of bone and joint prostheses.

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Most cited references 41

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On the mechanisms of biocompatibility.

David Williams (2008)

The manner in which a mutually acceptable co-existence of biomaterials and tissues is developed and sustained has been the focus of attention in biomaterials science for many years, and forms the foundation of the subject of biocompatibility. There are many ways in which materials and tissues can be brought into contact such that this co-existence may be compromised, and the search for biomaterials that are able to provide for the best performance in devices has been based upon the understanding of all the interactions within biocompatibility phenomena. Our understanding of the mechanisms of biocompatibility has been restricted whilst the focus of attention has been long-term implantable devices. In this paper, over 50 years of experience with such devices is analysed and it is shown that, in the vast majority of circumstances, the sole requirement for biocompatibility in a medical device intended for long-term contact with the tissues of the human body is that the material shall do no harm to those tissues, achieved through chemical and biological inertness. Rarely has an attempt to introduce biological activity into a biomaterial been clinically successful in these applications. This essay then turns its attention to the use of biomaterials in tissue engineering, sophisticated cell, drug and gene delivery systems and applications in biotechnology, and shows that here the need for specific and direct interactions between biomaterials and tissue components has become necessary, and with this a new paradigm for biocompatibility has emerged. It is believed that once the need for this change is recognised, so our understanding of the mechanisms of biocompatibility will markedly improve.

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FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly.

Donna J Webb, Karen Donais, Leanna Whitmore … (2004)

Cell migration is a complex, highly regulated process that involves the continuous formation and disassembly of adhesions (adhesion turnover). Adhesion formation takes place at the leading edge of protrusions, whereas disassembly occurs both at the cell rear and at the base of protrusions. Despite the importance of these processes in migration, the mechanisms that regulate adhesion formation and disassembly remain largely unknown. Here we develop quantitative assays to measure the rate of incorporation of molecules into adhesions and the departure of these proteins from adhesions. Using these assays, we show that kinases and adaptor molecules, including focal adhesion kinase (FAK), Src, p130CAS, paxillin, extracellular signal-regulated kinase (ERK) and myosin light-chain kinase (MLCK) are critical for adhesion turnover at the cell front, a process central to migration.

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mDia mediates Rho-regulated formation and orientation of stable microtubules.

Gregg G. Gundersen, A Palazzo, A Alberts … (2001)

Rho-GTPase stabilizes microtubules that are oriented towards the leading edge in serum-starved 3T3 fibroblasts through an unknown mechanism. We used a Rho-effector domain screen to identify mDia as a downstream Rho effector involved in microtubule stabilization. Constitutively active mDia or activation of endogenous mDia with the mDia-autoinhibitory domain stimulated the formation of stable microtubules that were capped and oriented towards the wound edge. mDia co-localized with stable microtubules when overexpressed and associated with microtubules in vitro. Rho kinase was not necessary for the formation of stable microtubules. Our results show that mDia is sufficient to generate and orient stable microtubules, and indicate that Dia-related formins are part of a conserved pathway that regulates the dynamics of microtubule ends.

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Author and article information

Contributors

Naoto Kobayashi: 81-89-960-5928 , 81-89-960-5931 , naoto@m.ehime-u.ac.jp

Journal

Journal ID (nlm-ta): Cell Mol Biol Lett

Journal ID (iso-abbrev): Cell. Mol. Biol. Lett

Title: Cellular & Molecular Biology Letters

Publisher: SP Versita (Heidelberg )

ISSN (Print): 1425-8153

ISSN (Electronic): 1689-1392

Publication date (Electronic): 9 March 2011

Publication date Collection: June 2011

Volume: 16

Issue: 2

Pages: 279-295

Affiliations

[1 ]GRID grid.255464.4, ISNI 0000000110113808, Department of Anatomy and Embryology, , Ehime University Graduate School of Medicine, ; Ehime, Japan

[2 ]GRID grid.255464.4, ISNI 0000000110113808, Medical Education Center, , Ehime University School of Medicine, ; Shitsukawa, To-on City, Ehime, 791-0295 Japan

[3 ]Shenyang Women and Children Health Center, Shenyang city, Liaoning, 110032 China

Article

Publisher ID: 6

DOI: 10.2478/s11658-011-0006-z

PMC ID: 6275969

PubMed ID: 21394446

SO-VID: d3f5a5df-746e-47f3-b185-8725ba641133

History

Date received : 22 October 2010

Date accepted : 2 March 2011

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Keywords: osteoblast,migration,rock inhibitor,cytoskeleton,stress fiber,focal contact,mlc phosphorylation

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Keywords: osteoblast, migration, rock inhibitor, cytoskeleton, stress fiber, focal contact, mlc phosphorylation

Rho kinase inhibitors stimulate the migration of human cultured osteoblastic cells by regulating actomyosin activity

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Gamma Delta T cells

Most cited references 41

On the mechanisms of biocompatibility.

FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly.

mDia mediates Rho-regulated formation and orientation of stable microtubules.

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