The imbalance between pro- and anti-inflammatory cytokines is a hallmark of auto-inflammatory bone disorders. A) The prolonged interaction between pyrin and PSTPIP1 in PAPA syndrome results in impaired inhibition of the NRLP3 inflammasome, resulting in enhanced IL-1β and IL-18 release after cleavage from pro-IL-1β/pro-IL-18 by activated caspase-1 (Casp.-1). B) In DIRA, a lack of functional IL-1 receptor antagonist (IL-1RA) results in impaired peripheral control of IL-1 signaling. C) In Majeed syndrome, Lipin2 deficiency may result in increased levels of fatty acids that may be recognized by TLR-2 and -4, resulting in Jun kinase (JNK) activation and subsequent pro-inflammatory signaling. D) In CRMO monocytes, impaired ERK1/2 activation results in reduced Sp-1 recruitment and decreased histone H3 phosphorylation (H3S10P) of the IL10 promoter. This molecular defect results in a failure to express IL-10 and an imbalance between pro- and anti-inflammatory cytokines.