LIM Homeobox Transcription Factor 1-β Expression is Upregulated in Patients with Osteolysis after Total Ankle Arthroplasty and Inhibits Receptor Activator of Nuclear Factor- <b>κ</b>B Ligand-Induced Osteoclast Differentiation <i>in Vitro</i>

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Abstract

Background

Osteolysis is one of the most common problems that occurs after total hip and knee arthroplasty and has recently become a significant problem after total ankle arthroplasty (TAA). In this study, we investigated the role of LIM homeobox transcription factor 1-β (Lmx1b) in osteoclast differentiation. By evaluating the expression profiles associated with osteolysis following TAA treatment, Lmx1b was found to be differentially expressed in patients with osteolysis after TAA.

Methods

To identify the important genes associated with osteolysis after TAA, RNA sequencing was performed by analyzing 8 patient samples: 5 primary TAA samples (control group) and 3 TAA samples revised for flexion instability (osteolysis group). By analyzing the differentially expressed genes and gene ontologies, Lmx1b expression was found to be upregulated in the osteolysis group compared to that in the control group. Focusing on the role of Lmx1b in bone cells, Lmx1b was overexpressed by a retrovirus in osteoclast precursor cells. The cultured cells were stained with tartrate-resistant acid phosphatase, and the expression of osteoclast-related genes was analyzed using real-time polymerase chain reaction.

Results

Lmx1b overexpression in osteoclast precursors suppresses osteoclast formation and resorptive activity. The expression of osteoclast marker genes was significantly reduced during osteoclast differentiation by Lmx1b overexpression. Furthermore, Lmx1b is associated with nuclear factor of activated T cells 1 (NFATc1) and inhibited NFATc1 translocation into the nucleus.

Conclusions

These results provide novel insights into the anti-bone resorptive effect of Lmx1b on osteolysis after TAA and may lead to the development of effective preventative and therapeutic strategies for peri-implant osteolysis.

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Most cited references 26

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Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.

Hiroshi Takayanagi, Sunhwa Kim, Takako Koga … (2002)

Signaling by RANKL is essential for terminal differentiation of monocytes/macrophages into osteoclasts. The TRAF6 and c-Fos signaling pathways both play important roles downstream of RANKL. We show here that RANKL selectively induces NFATc1 expression via these two pathways. RANKL also evokes Ca(2+) oscillations that lead to calcineurin-mediated activation of NFATc1, and therefore triggers a sustained NFATc1-dependent transcriptional program during osteoclast differentiation. We also show that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL.

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NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP).

Seoung-Ae Lee, Nacksung Kim, Yongwon Choi … (2007)

NFATc1 has been characterized as a master regulator of nuclear factor kappaB ligand-induced osteoclast differentiation. Herein, we demonstrate a novel role for NFATc1 as a positive regulator of nuclear factor kappaB ligand-mediated osteoclast fusion as well as other fusion-inducing factors such as TNF-alpha. Exogenous overexpression of a constitutively active form of NFATc1 in bone marrow-derived monocyte/macrophage cells (BMMs) induces formation of multinucleated osteoclasts as well as the expression of fusion-mediating molecules such as the d2 isoform of vacuolar ATPase V(o) domain (Atp6v0d2) and the dendritic cell-specific transmembrane protein (DC-STAMP). Moreover, inactivation of NFATc1 by cyclosporin A treatment attenuates expression of Atp6v0d2 and DC-STAMP and subsequent fusion process of osteoclasts. We show that NFATc1 binds to the promoter regions of Atp6v0d2 and DC-STAMP in osteoclasts and directly induces their expression. Furthermore, overexpression of Atp6v0d2 and DC-STAMP rescues cell-cell fusion of preosteoclasts despite reduced NFATc1 activity. Our data indicate for the first time that the NFATc1/Atp6v0d2 and DC-STAMP signaling axis plays a key role in the osteoclast multinucleation process, which is essential for efficient bone resorption.

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The cellular and molecular biology of periprosthetic osteolysis.

Panagiotis Koulouvaris, Thomas Sculco, Hollis G. Potter … (2006)

The generation of prosthetic implant wear after total joint arthroplasty is recognized as the major initiating event in development of periprosthetic osteolysis and aseptic loosening, the leading complication of this otherwise successful surgical procedure. We review current concepts of how wear debris causes osteolysis, and report ideas for prevention and treatment. Wear debris primarily targets macrophages and osteoclast precursor cells, although osteoblasts, fibroblasts, and lymphocytes also may be involved. Molecular responses include activation of MAP kinase pathways, transcription factors (including NFkappaB), and suppressors of cytokine signaling. This results in up-regulation of proinflammatory signaling and inhibition of the protective actions of antiosteoclastogenic cytokines such as interferon gamma. Strategies to reduce osteolysis by choosing bearing surface materials with reduced wear properties should be balanced by awareness that reducing particle size may increase biologic activity. There are no approved treatments for osteolysis despite the promise of therapeutic agents against proinflammatory mediators (such as tumor necrosis factor) and osteoclasts (bisphosphonates and molecules blocking receptor activator of NFkappaB ligand [RANKL] signaling) shown in animal models. Considerable efforts are underway to develop such therapies, to identify novel targets for therapeutic intervention, and to develop effective outcome measures.

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Author and article information

Journal

Journal ID (nlm-ta): J Bone Metab

Journal ID (iso-abbrev): J Bone Metab

Title: Journal of Bone Metabolism

Publisher: The Korean Society for Bone and Mineral Research

ISSN (Print): 2287-6375

ISSN (Electronic): 2287-7029

Publication date (Print): August 2022

Publication date (Electronic): 31 August 2022

Volume: 29

Issue: 3

Pages: 165-174

Affiliations

[1 ]Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea

[2 ]Department of Orthopedic Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea

Author notes

Corresponding author: Nacksung Kim, Department of Pharmacology, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju 61469, Korea, Tel: +82-61-379-2835, Fax: +82-61-373-6974, E-mail: nacksung@ 123456jnu.ac.kr

Author information

Kabsun Kim https://orcid.org/0000-0002-8320-5030

Jeong Eun Han https://orcid.org/0000-0002-0515-1890

Keun-Bae Lee https://orcid.org/0000-0003-3808-2649

Nacksung Kim https://orcid.org/0000-0002-8132-3981

Article

Publisher ID: jbm-2022-29-3-165

DOI: 10.11005/jbm.2022.29.3.165

PMC ID: 9511124

PubMed ID: 36153852

SO-VID: 93e88583-cfb7-4af0-aedd-ca63bec33901

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 12 July 2022

Date revision received : 20 July 2022

Date accepted : 21 July 2022

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LIM Homeobox Transcription Factor 1-β Expression is Upregulated in Patients with Osteolysis after Total Ankle Arthroplasty and Inhibits Receptor Activator of Nuclear Factor- κB Ligand-Induced Osteoclast Differentiation in Vitro

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SICOT-J (Orthopedic surgery and traumatology)

Most cited references 26

Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.

NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP).

The cellular and molecular biology of periprosthetic osteolysis.

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