ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiation

Juri Nakata; Yosuke Akiba; Jun Nihara; Lay Thant; Kaori Eguchi; Hiroko Kato; Kenji Izumi; Mariko Ohkura; Masanori Otake; Yoshito Kakihara; Isao Saito; Makio Saeki

doi:10.1016/j.bbrc.2020.03.033

ROCK inhibitors enhance bone healing by promoting osteoclastic and osteoblastic differentiation

Biochem Biophys Res Commun. 2020 Jun 4;526(3):547-552. doi: 10.1016/j.bbrc.2020.03.033. Epub 2020 Mar 17.

Authors

Juri Nakata¹, Yosuke Akiba², Jun Nihara³, Lay Thant¹, Kaori Eguchi², Hiroko Kato⁴, Kenji Izumi⁵, Mariko Ohkura³, Masanori Otake³, Yoshito Kakihara⁶, Isao Saito³, Makio Saeki⁷

Affiliations

¹ Division of Orthodontics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan; Division of Dental Pharmacology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan.
² Division of Bio-Prosthodontics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan.
³ Division of Orthodontics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan.
⁴ Division of Biomimetics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan; Research Center for Advanced Oral Science, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan.
⁵ Division of Biomimetics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan.
⁶ Division of Dental Pharmacology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan. Electronic address: kakihara@dent.niigata-u.ac.jp.
⁷ Division of Dental Pharmacology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan.

PMID: 32192772
DOI: 10.1016/j.bbrc.2020.03.033

Abstract

Osteoclast and osteoblast are essential for proper bone development and remodeling as well as recovery of bone fracture. In this study, we seek chemical compounds that enhance turnover of bone metabolism for promoting bone healing. First, we screen a chemical library which includes 378 compounds by using murine pre-osteoclastic RAW264.7 cells to identify compounds that promote osteoclastic differentiation. We find that two ROCK (Rho-associated coiled-coil kinase) inhibitors, HA-1077 (Fasudil) and Y-27632, enhance osteoclastogenesis. Subsequently, we identify that these two compounds also increase osteoblastic differentiation of MC3T3-E1 cells. Finally, our in vivo experiment shows that the local administration of ROCK inhibitors accelerate the bone healing of the rat calvarial defect.

Keywords: Bone healing; Osteoblastosgenesis; Osteoclastogenesis; ROCK inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / chemistry
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
Amides / chemistry
Amides / pharmacology*
Amides / therapeutic use
Animals
Cell Differentiation
Cell Line
Fracture Healing / drug effects
Male
Mice
Osteoblasts / cytology
Osteoblasts / drug effects
Osteoblasts / metabolism
Osteoclasts / cytology
Osteoclasts / drug effects
Osteoclasts / metabolism
Osteogenesis / drug effects*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Pyridines / chemistry
Pyridines / pharmacology*
Pyridines / therapeutic use
RAW 264.7 Cells
Rats
Rats, Sprague-Dawley
Skull / drug effects
Skull / injuries
Skull / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology
rho-Associated Kinases / antagonists & inhibitors*
rho-Associated Kinases / metabolism

Substances

Amides
Protein Kinase Inhibitors
Pyridines
Small Molecule Libraries
Y 27632
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
rho-Associated Kinases
fasudil