Hydrogen sulfide biosynthesis is impaired in the osteoarthritic joint

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.

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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

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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.

Funding

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).

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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.

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Correspondence to Elena F. Burguera or Francisco J. Blanco.

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Burguera, E.F., Vela-Anero, Á., Gato-Calvo, L. et al. Hydrogen sulfide biosynthesis is impaired in the osteoarthritic joint. Int J Biometeorol 64, 997–1010 (2020). https://doi.org/10.1007/s00484-019-01823-w

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Keywords

  • Osteoarthritis
  • Hydrogen sulfide
  • Human articular cartilage
  • Serum
  • Mitochondria
  • Sulfurous thermal waters