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Fig. 1 | Molecular and Cellular Pediatrics

Fig. 1

From: The molecular pathophysiology of chronic non-bacterial osteomyelitis (CNO)—a systematic review

Fig. 1

Molecular pathophysiology of CRMO. a The sensing of danger- and pathogen-associated molecular patterns (DAMPS and PAMPS) occurs by pattern recognition receptors (PRRs), such as membrane-associated Toll-like receptors (TLRs) and cytoplasmic-localized NOD-like receptors (NLRs). TLR4 activation by lipopolysaccharide (LPS) results in the activation of mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and Jun kinase (JNK). In response to the recognition of danger signals, multiprotein complexes, so-called inflammasomes, are activated. The NLRP3 inflammasome comprises NLRP3, ASC, and procaspase-1. Inflammasomes mediate caspase-1 activation, which results in cleavage of pro-IL-1β into its active from IL-1β. In monocytes from CRMO patients, impaired ERK1/2 signaling results in failure to express IL-10 and IL-19. Reduced expression of IL-10 and IL-19 contributes to inflammasome activation and IL-1β release. Pro-inflammatory cytokines IL-1β, IL-6, IL-20, and TNFα increase the interaction of RANK receptors on osteoclast precursor cells with their soluble ligand RANKL, inducing osteoclast activation and differentiation. b IL10 promoter polymorphisms rs1800896 (-1082A>G), rs1800871 (-819T>C), and rs1800872 (-592A>C) form distinct haplotypes (GCC, ACC, and ATA) that determine transcription factor recruitment. (MAPK mitogen-activated protein kinase; CRMO chronic recurrent multifocal osteomyelitis; ERK1/2 extracellular signal-regulated kinases 1 and 2; TLR Toll-like receptor; IL interleukin; JNK Jun kinase; TNF tumor necrosis factor; NF-κB nuclear factor-κB; Casp1 caspase-1; PAMP pathogen-associated molecular pattern; DAMP danger-associated molecular pattern; RANK receptor activator of nuclear factor-κB; RANKL RANK ligand)

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