HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis

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Abstract

Background

The aim of this study was to evaluate whether histone deacetylase 4 S246/467/632A mutant (m-HDAC4) has enhanced function at histone deacetylase 4 (HDAC4) to attenuate cartilage degeneration in a rat model of osteoarthritis (OA).

Methods

Chondrocytes were infected with Ad-m- HDAC4-GFP or Ad- HDAC4-GFP for 24 h, incubated with interleukin-1β (IL-1β 10 ng/mL) for 24 h, and then measured by RT-qPCR. Male Sprague-Dawley rats ( n = 48) were randomly divided into four groups and transduced with different vectors: ACLT/Ad- GFP, ACLT/Ad- HDAC4-GFP, ACLT/Ad-m- HDAC4-GFP, and sham/Ad- GFP. All rats received intra-articular injections 48 h after the operation and every 3 weeks thereafter. Cartilage damage was assessed using radiography and Safranin O staining and quantified using the OARSI score. The hypertrophic and anabolic molecules were detected by immunohistochemistry and RT-qPCR.

Results

M- HDAC4 decreased the expression levels of Runx-2, Mmp-13, and C ol 10a1, but increased the levels of C ol 2a1 and ACAN more effectively than HDAC4 in the IL-1β-induced chondrocyte OA model; upregulation of HDAC4 and m -HDAC4 in the rat OA model suppressed Runx-2 and MMP-13 production, and enhanced Col 2a1 and ACAN synthesis. Stronger Safranin O staining was detected in rats treated with m- HDAC4 than in those treated with HDAC4. The resulting OARSI scores were lower in the Ad-m- HDAC4 group (5.80 ± 0.45) than in the Ad- HDAC4 group (9.67 ± 1.83, P = 0.045). The OARSI scores were highest in rat knees that underwent ACLT treated with Ad- GFP control adenovirus vector (14.93 ± 2.14, P = 0.019 compared with Ad- HDAC4 group; P = 0.003 compared with Ad-m- HDAC4 group). Lower Runx-2 and MMP-13 production, and stronger Col 2a1 and ACAN synthesis were detected in rats treated with m- HDAC4 than in those treated with HDAC4.

Conclusions

M-HDAC4 repressed chondrocyte hypertrophy and induced chondrocyte anabolism in the nucleus. M-HDAC4 was more effective in attenuating articular cartilage damage than HDAC4.

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Most cited references 29

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Osteoarthritis cartilage histopathology: grading and staging.

K.P.H. Pritzker, S. Gay, S.A Jimenez … (2006)

Current osteoarthritis (OA) histopathology assessment methods have difficulties in their utility for early disease, as well as their reproducibility and validity. Our objective was to devise a more useful method to assess OA histopathology that would have wide application for clinical and experimental OA assessment and would become recognized as the standard method. An OARSI Working Group deliberated on principles, standards and features for an OA cartilage pathology assessment system. Using current knowledge of the pathophysiology of OA morphologic features, a proposed system was presented at OARSI 2000. Subsequently, this was widely circulated for comments amongst experts in OA pathology. An OA cartilage pathology assessment system based on six grades, which reflect depth of the lesion and four stages reflecting extent of OA over the joint surface was developed. The OARSI cartilage OA histopathology grading system appears consistent and simple to apply. Further studies are required to confirm the system's utility.

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Osteoarthritis: an update with relevance for clinical practice.

Johannes Bijlsma, Francis Berenbaum, Floris Lafeber (2011)

Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much help from disease-modifying drugs. Despite efforts over the past decades to develop markers of disease, still-imaging procedures and biochemical marker analyses need to be improved and possibly extended with more specific and sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients according to their prognosis, and to follow the course of disease and treatment effectiveness. In the coming years, a better definition of osteoarthritis is expected by delineating different phenotypes of the disease. Treatment targeted more specifically at these phenotypes might lead to improved outcomes. Copyright © 2011 Elsevier Ltd. All rights reserved.

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The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.

Xiang-Jiao Yang, Edward Seto (2008)

Protein lysine deacetylases have a pivotal role in numerous biological processes and can be divided into the Rpd3/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3/Hda1 family contains 11 members, traditionally referred to as histone deacetylases (HDAC) 1-11, which are further grouped into classes I, II and IV. Whereas most class I HDACs are subunits of multiprotein nuclear complexes that are crucial for transcriptional repression and epigenetic landscaping, class II members regulate cytoplasmic processes or function as signal transducers that shuttle between the cytoplasm and the nucleus. Little is known about class IV HDAC11, although its evolutionary conservation implies a fundamental role in various organisms.

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Author and article information

Contributors

Pengcui Li:

ORCID: http://orcid.org/0000-0003-2044-4234

doctorli3365646@163.com

Journal

Journal ID (nlm-ta): BMC Musculoskelet Disord

Journal ID (iso-abbrev): BMC Musculoskelet Disord

Title: BMC Musculoskeletal Disorders

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2474

Publication date (Electronic): 3 January 2022

Publication date PMC-release: 3 January 2022

Publication date Collection: 2022

Volume: 23

Electronic Location Identifier: 8

Affiliations

[1 ]Department of Orthopaedics, Shanxi Bethune Hospital, Longcheng Road 99, Taiyuan, 030032 China

[2 ]GRID grid.452845.a, Department of Orthopaedics, , The Second Hospital of Shanxi Medical University, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, ; Wuyi Road 382, Taiyuan, 030001 China

Author information

Pengcui Li http://orcid.org/0000-0003-2044-4234

Article

Publisher ID: 4947

DOI: 10.1186/s12891-021-04947-6

PMC ID: 8725337

PubMed ID: 34980076

SO-VID: 6ffb49cf-a76a-49de-a747-58f877ef2604

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 28 April 2021

Date accepted : 8 December 2021

Funding

Funded by: Osteoarthritis Biological Sample Resource Sharing Service Platform Construction Project of Shanxi Province

Award ID: 201705D121010

Funded by: FundRef http://dx.doi.org/10.13039/501100010909, Young Scientists Fund;

Award ID: 81601949

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: histone deacetylase 4 s246/467/632a mutant,chondrocyte hypertrophy,nucleus translocation,osteoarthritis

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ScienceOpen disciplines: Orthopedics

Keywords: histone deacetylase 4 s246/467/632a mutant, chondrocyte hypertrophy, nucleus translocation, osteoarthritis

HDAC4 mutant represses chondrocyte hypertrophy by locating in the nucleus and attenuates disease progression of posttraumatic osteoarthritis

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Abstract

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Most cited references 29

Osteoarthritis cartilage histopathology: grading and staging.

Osteoarthritis: an update with relevance for clinical practice.

The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.

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