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Bone Abstracts (2019) 7 LB5 | DOI: 10.1530/boneabs.7.LB5

ICCBH2019 Late Breaking Abstracts (1) (10 abstracts)

Chronic recurrent multifocal osteomyelitis in children with hypophosphatasia explained by anti-inflammatory nucleotidase activity of tissue nonspecific alkaline phosphatase in mesenchymal and hematopoietic cells

Laurence Bessueille 1 , Anne Briolay 1 , Juna Como 1 , Cylia Mansouri 1 , Marie Gleizes 2 , Alaeddine El Jamal 1 , René Buchet 1 , Charles Dumontet 3 , Eva-Laure Matera 3 , Etienne Mornet 4 , Jose Luis Millan 5 , Caroline Fonta 2 & David Magne 1

1University of Lyon ICBMS CNRS 5246, Villeurbanne, France; 2CERCO UMR CNRS 5549 Université de Toulouse, Toulouse, France; 3CRCL, INSERM U1052, CNRS UMR 5286, CLB, UCBL, Lyon, France; 4Unité de Génétique Constitutionnelle, Centre Hospitalier de Versailles, Le Chesnay, France; 5Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

Deficiency in tissue nonspecific alkaline phosphatase (TNAP) causes hypophosphatasia (HPP), which is mainly characterized by skeletal hypomineralization. TNAP promotes mineralization by dephosphorylating the mineralization inhibitor inorganic pyrophosphate (PPi), which is generated from adenosine triphosphate (ATP) by ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Chronic recurrent multifocal osteomyelitis (CRMO), a sterile bone auto-inflammatory disease, has been described in childhood HPP (Girschick, BMC Pediatr 2007), but how TNAP deficiency triggers CRMO remains unknown. Interestingly, several chronic non-bacterial osteomyelitis related monogenic auto-inflammatory diseases rely on pathological IL-1β activation. Deficiency of IL-1 receptor antagonist (DIRA) or cryopyrin-associated periodic syndrome (CASP, NLRP3 activating mutations) generate IL-1β-associated osteomyelitis. Since NLRP3-dependent secretion of IL-1β relies on extracellular ATP release and autocrine binding to purinergic receptors, we hypothesized that CRMO in HPP children is due to the lack of extracellular ATP dephosphorylation by TNAP and pathological activation of NLRP3. We first observed by quantitative PCR that bones from 7-day-old Tnap+/− mice presented increased levels of Il-1β and Il-6 and decreased levels of the anti-inflammatory Il-10 cytokine as compared with Tnap+/+ mice. Tnap levels were higher than those of the nucleotidases Npp1, Cd39 and Cd73 in bones of WT 7-day-old mice, as well as in primary mouse osteoblasts and hypertrophic chondrocytes. In these cells, TNAP inhibition with MLS-0038949 exacerbated IL-6 production in response to pro-inflammatory signals. This was accompanied by decreased hydrolysis of ATP and AMP. We however observed that mouse and human mesenchymal cells are unable to activate IL-1β in response to ATP. Since NLRP3 activation in myeloid cells but not in mesenchymal cells was reported to induce osteomyelitis (Wang, Sci Rep 2017), we explored the function of TNAP in neutrophils, which are the leukocytes that have the highest TNAP activity. We found that TNAP inhibition not only exacerbated IL-1β secretion in LPS-activated human neutrophils, but also increased their survival. Collectively, these results demonstrate that TNAP is an anti-inflammatory nucleotidase in mesenchymal cells and neutrophils, and that its deficiency in neutrophils but not mesenchymal cells, is likely to result in pathological IL-1β activation and CRMO.

Disclosure: The authors declared no competing interests.

Volume 7

9th International Conference on Children's Bone Health


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