Fig. 3.

Molecular pathophysiology of CNO/CRMO. Inflammation is a potent and undirected defense mechanism against exogenous pathogens or endogenous danger signals (such as infections, tissue damage). The sensing of danger signals occurs by pattern recognition receptors (PRRs), such as the membrane-associated Toll-like receptors (TLRs) and the predominantly cytoplasmic localized NOD-like receptors (NLRs). After recognition of danger signals by monocytes/macrophages, multiprotein complexes, referred to as inflammasomes are activated. The NLRP3 inflammasome comprises NLRP3, ASC, and procaspase-1. After inflammasome activation, caspase-1 cleaves pro-IL-1β and leads to the secretion of active IL-1β. In monocytes from CRMO patients, MAP kinase Erk1 and 2 signaling is impaired, resulting in reduced expression of the immune regulatory cytokines IL-10 and IL-19. JNK and p38 MAPK are unaffected, leading to the expression of pro-inflammatory cytokines (TNFα, IL-6, IL-1β, IL-20). Reduced expression of IL-10 and IL-19 contributes to increased inflammasome activation and subsequent IL-1β release. Pro-inflammatory cytokines TNFα, IL-6, IL-20, and IL-1β increase the interaction of membrane RANK receptors with their soluble ligand RANKL on osteoclast precursor cells and induce osteoclast differentiation and activation.MAPK: mitogen-activated protein kinase; CRMO: chronic recurrent multifocal osteomyelitis; Erk1: extracellular signal-regulated kinase-1; 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