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Biomaterials. 2019 Feb;192:62-74. doi: 10.1016/j.biomaterials.2018.11.003. Epub 2018 Nov 3.

Neuronal PAS domain 2 (Npas2) facilitated osseointegration of titanium implant with rough surface through a neuroskeletal mechanism.

Author information

1
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA; Department of Oral Rehabilitation, Section of Oral Implantology, Fukuoka Dental College, Fukuoka, Japan.
2
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA; Department of Oral and Maxillofacial Implantology, Tokyo Dental College, Tokyo, Japan.
3
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA.
4
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA; Regenerative Bioengineering and Repair Laboratory, Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
5
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA; Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan.
6
Department of Psychiatry & Biobehavioral Science, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
7
Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA, USA. Electronic address: inishimura@dentistry.ucla.edu.

Abstract

Titanium (Ti) biomaterials have been applied to a wide range of implantable medical devices. When placed in bone marrow, Ti-biomaterials integrate to the surrounding bone tissue by mechanisms that are not fully understood. We have previously identified an unexpected upregulation of circadian clock molecule neuronal PAS domain 2 (Npas2) in successfully integrated implant with a rough surface. This study aimed to elucidate the molecular mechanism of osseointegration through determining the role of Npas2. Human bone marrow stromal cells (BMSC) that were cultured on a Ti disc with SLA surface exhibited increased NPAS2 expression compared to BMSC cultured on a machined surface. A mouse model was developed in which miniature Ti implants were surgically placed into femur bone marrow. The implant push-out test and bone-to-implant contact measurements demonstrated the establishment of osseointegration in 3 weeks. By contrast, in Npas2 functional knockout (KO) mice, the implant push-out value measured for SLA surface Ti implant was significantly decreased. Npas2 KO mice demonstrated normal femur bone structure surrounding the Ti implant; however, the recovered implants revealed abnormal remnant mineralized tissue, which lacked dense collagen architecture typically found on recovered implants from wild type mice. To explore the mechanisms leading to the induced Npas2 expression, an unbiased chemical genetics analysis was conducted using mouse BMSC carrying an Npas2-reporter gene for high throughput screening of Library of Pharmacologically Active Compounds. Npas2 modulating compounds were found clustered in regulatory networks of the α2-adrenergic receptor and its downstream cAMP/CREB signaling pathway. Mouse primary BMSC exposed to SLA Ti disc significantly increased the expression of α2-adrenergic receptors, but the expression of β2-adrenergic receptor was unaffected. Our data provides the first evidence that peripheral clock gene component Npas2 plays a role in facilitating the enhanced osseointegration through neuroskeletal regulatory pathways induced by BMSC in contact with rough surface Ti implant.

KEYWORDS:

Chemical genetics; Endosseous implant; Neuroskeletal regulation; Npas2; Osseointegration; Titanium biomaterials

PMID:
30428407
PMCID:
PMC6389329
[Available on 2020-02-01]
DOI:
10.1016/j.biomaterials.2018.11.003

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