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Hydrogen sulfide biosynthesis is impaired in the osteoarthritic joint

  • Elena F. BurgueraEmail author
  • Ángela Vela-Anero
  • Lucía Gato-Calvo
  • Carlos Vaamonde-García
  • Rosa Meijide-Faílde
  • Francisco J. BlancoEmail author
Special Issue: Balneology

Abstract

Osteoarthritis (OA) is the most common form of arthritis and it is a leading cause of disability in the elderly. Its complete etiology is not known although there are several metabolic, genetic, epigenetic, and local contributing factors involved. At the moment, there is no cure for this pathology and treatment alternatives to retard or stop its progression are intensively being sought. Hydrogen sulfide (H2S) is a small gaseous molecule and is present in sulfurous mineral waters as its active component. Data from recent clinical trials shows that balneotherapy (immersion in mineral and/or thermal waters from natural springs) in sulfurous waters can improve OA symptoms, in particular, pain and function. Yet, the underlying mechanisms are poorly known. Hydrogen sulfide is also considered, with NO and CO, an endogenous signaling gasotransmitter. It is synthesized endogenously with the help of three enzymes, cystathionine gamma-lyase (CTH), cystathionine beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST). Here, the expression of these three enzymes was demonstrated by quantitative real-time polymerase chain reaction (qRT-PCR) and their protein abundance [by immunohistochemistry and Western blot (WB)] in human articular cartilage. No significant differences were found in CBS or CTH expression or abundance, but mRNA and protein levels of 3-MPST were significantly reduced in cartilage form OA donors. Also, the biosynthesis of H2S from OA cartilage, measured with a specific microelectrode, was significantly lower than in OA-free tissue. Yet, no differences were found in H2S concentration in serum from OA patients and OA-free donors. The current results suggest that reduced levels of the mitochondrial enzyme 3-MPST in OA cartilage might be, at least in part, responsible for a reduction in H2S biosynthesis in this tissue and that impaired H2S biosynthesis in the joint might be a contributing factor to OA. This could contribute to explain why exogenous supplementation of H2S, for instance with sulfurous thermal water, has positive effects in OA patients.

Keywords

Osteoarthritis Hydrogen sulfide Human articular cartilage Serum Mitochondria Sulfurous thermal waters 

Abbreviations

3-MP

3-Mercaptopyruvate

3-MPST

3-Mercaptopyruvate sulfurtransferase

AD

Alzheimer’s disease

AECOPD

Acute exacerbation of COPD

CAT

Cysteine aminotransferase

CBS

Cystathionine β-synthase

cDNA

Complementary deoxyribonucleic acid

CAEIG

Galician Research Ethics Committee (Comité Autonómico de Ética da Investigación de Galicia)

CHD

Coronary heart disease

CO

Carbon monoxide

COPD

Chronic obstructive pulmonary disease

CTH

Cystathionine γ-lyase

CVD

Cerebrovascular disease

DMPD

N,N-dimethyl-p-phenylenediamine

H2S

Hydrogen sulfide

IHC

Immunohistochemistry

IL

Interleukin

HPRT1

Hypoxanthine-guanine phosphoribosyltransferase

MMPs

Matrix metalloproteinases

mRNA

Messenger RNA

N

Normal (non-OA), healthy control

n

Sample size

NADH

Nicotinamide adenine dinucleotide

NADPH

Nicotinamide adenine dinucleotide phosphate

NaSH

Sodium hydrosulfide

NO

Nitric oxide

NRF2

Nuclear factor erythroid 2–related factor 2

OA

Osteoarthritis

OARSI

Osteoarthritis Research Society International

PAGE

Polyacrylamide gel electrophoresis

RA

Rheumatoid arthritis

RNA

ribonucleic acid

ROS

Reactive oxygen species

RT

Room temperature

SDS

Sodium dodecyl sulfate

SE

Standard error of the mean

SOD

Superoxide dismutase

TAC

Total anti-oxidant capacity

TBP

Tata-box-binding protein

Treg

Regulatory T cells

VD

Vascular dementia

WB

Western blot

Notes

Acknowledgments

Authors want to express their gratitude to the patients that made possible this study and to the Rheumatology and Orthopedic Services of the University Hospital A Coruña for their help in obtaining the human samples.

Authors’ contributions

All authors were involved in drafting or critically reading the manuscript for important intellectual content, and all authors approved the final version. Conception and design: EF Burguera, R Meijide-Failde, FJ Blanco. Data acquisition: Á Vela-Anero, L. Gato-Calvo, C Vaamonde-García. Analysis and interpretation of data: Á Vela-Anero, EF Burguera, FJ Blanco. Obtaining of funding: R Meijide-Failde, FJ Blanco.

Funding information

This work was financially supported in part through projects (PI12/00329; PI16/02124; RETIC-RIER-RD12/0009/0018; and Proteo-Red/ISCIII) from ISCIII- General Subdirection of Assesment and Promotion of the Research – European Regional Development Fund (FEDER) “A way of making Europe”, and in part by Grant IN607A 2017/11 from Xunta de Galicia. CIBER-BBN is a national initiative of ISCIII. LGC is financially supported by contract FPU13/06041 (Ministerio de Educación, Cultura y Deporte). CVG was financially supported by Xunta de Galicia (Postdoctoral contract POS-A/2013/206). EFB is financially supported by Grant PMP15/00032 from Fondo Investigación Sanitaria-Spain (ISCIII).

Compliance with ethical standards

Disclaimer

The funders did not contribute to data collection, analysis or interpretation of the data, manuscript preparation, or submission.

Conflict of interest

The authors declare that they have no conflict of interest.

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© ISB 2019

Authors and Affiliations

  1. 1.Grupo de Investigación en Reumatología (GIR), Agrupación Estratégica CICA-INIBIC, Complexo Hospitalario Universitario A Coruña, SergasInstituto de Investigación Biomédica A Coruña-INIBICA CoruñaSpain
  2. 2.CIBER-BBNMadridSpain
  3. 3.Grupo de Terapia Celular e Medicina Regenerativa, Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña, SergasUniversidad de A CoruñaA CoruñaSpain
  4. 4.Grupo de Investigación en Reumatología (GIR), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario A Coruña, SergasUniversidad de A CoruñaA CoruñaSpain
  5. 5.ProteoRed/ISCIIIMadridSpain

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