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How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases?

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Abstract

Hypophosphatasia (HP) is a rare inborn error of bone and mineral metabolism characterized by a defect in the tissue non-specific alkaline phosphatase (TNSALP) gene. Calcium pyrophosphate dihydrate (CPPD) crystals are known to accumulate as substrates of TNSALP in tissues and joints of patients with HP. In CPPD-induced arthritis these crystals are known to induce an inflammatory response. HP patients do suffer from pain in their lower extremities. However, it is not clear whether CPPD crystals contribute to these musculoskeletal complaints in HP. As long as there is no curative treatment of HP, symptomatic treatment in order to improve clinical features, especially with regard to pain and physical activity, is of major interest to the patients. Knowledge of the mechanisms underlying crystal-induced cell activation, however, is limited. Here we describe recent advances in elucidating the signal transduction pathways activated by CPPD crystals as endogenous “danger signals”. Recent investigations provided evidence that Toll/interleukin-1 receptor (TIR) domain containing receptors including Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R), as well as the triggering receptor expressed on myeloid cells 1 (TREM-1) and the NACHT-leucin rich repeat and pyrin-domain-containing protein (NALP3) containing inflammasome are essentially involved in acute CPPD crystal-induced inflammation. These receptors are considered in part as components of the innate immune system. Further studies are needed to improve our understanding of the pathophysiological mechanisms leading to inflammation and tissue destruction associated with deposition of microcrystals. They might support the development of new therapeutic strategies for crystal-induced inflammation. Eventually, patients with HP might as well profit from such strategies addressing these metabolic disorders secondary to the gene defect.

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Abbreviations

AP-1:

Activating protein 1

ASC:

Apoptosis-associated speck-like protein

CAPS:

Cryopyrin-associated periodic syndrome

CC:

Chondrocalcinosis

CINCA:

Chronic infantile neurologic cutaneous and articular syndrome

CNO:

Chronic non-bacterial osteomyelitis

CPPD:

Calcium pyrophosphate dihydrate

CRMO:

Chronic recurrent multifocal osteomyelitis

ERK 1/2:

Extracellular signal-regulated kinase 1/2

FCAS:

Familial cold autoinflammatory syndrome

HP:

Hypophosphatasia

IKK:

IкB kinase

IL-1R:

Interleukin-1 receptor

iNOS:

Inducible nitric oxide synthetase

IRAK:

IL-1-associated kinase

JNK:

c-Jun N-terminal kinase

LPS:

Lipopolysaccharide

LRR:

Leucin-rich repeats

MAP:

Mitogen-activated protein kinase

MDP:

Muramyl dipeptide

MWS:

Muckle-Wells syndrome

MMP:

Matrix metalloproteinase

MSU:

Monosodium urate

MyD88:

Myeloid differentiation factor 88

NALP3:

NACHT-leucin rich repeat and pyrin-domain-containing protein

NLR:

Nod-like receptor

NO:

Nitric oxide

NOD:

Nucleotide-binding oligomerization domain

NOMID:

Neonatal onset multisystem inflammatory disease

NSAID:

Non-steroidal anti-inflammatory drugs

PAMP:

Pathogen-associated molecular pattern

PL:

Pyridoxal

PLP:

Pyridoxal 5′-phosphate

PPi:

Inorganic pyrophosphate

PRR:

Pathogen recognition receptor

PTH:

Parathyreoid hormone

PYD:

Pyrin domain

RLR:

Retinoic acid-like receptor

TIR:

Toll/interleukin-1 receptor

TIRAP:

TIR domain-containing adaptor protein

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNSALP:

Tissue non-specific alkaline phosphatase

TRAF6:

TNF receptor-associated factor 6

TREM-1:

Triggering receptor expressed on myeloid cells 1

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Authors and Affiliations

  1. Children’s hospital, Section of Pediatric Rheumatology, Immunology and Infectious Diseases, University of Würzburg, Josef-Schneider-Str. 2, 97090, Würzburg, Germany

    C. Beck, H. Morbach, P. Richl & H. J. Girschick

  2. Department of Radiology, Section of Pediatric Radiology, University of Würzburg, Josef-Schneider-Strasse 2, 97080, Würzburg, Germany

    M. Stenzel

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  1. C. Beck
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  2. H. Morbach
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Correspondence to H. J. Girschick.

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Beck, C., Morbach, H., Richl, P. et al. How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases?. Rheumatol Int 29, 229–238 (2009). https://doi.org/10.1007/s00296-008-0710-9

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  • DOI: https://doi.org/10.1007/s00296-008-0710-9

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