Novel Majeed syndrome causing LPIN2 mutations link bone inflammation to inflammatory M2 macrophages and accelerated osteoclastogenesis

Objective We identified novel heterozygous LPIN2 mutations in a Majeed patient and characterize the pathomechanisms that lead to the development of sterile osteomyelitis. Methods Targeted genetic analysis, and functional studies assessing monocyte responses, macrophage differentiation and osteoclastogenesis were conducted to compare the pathogenesis of Majeed syndrome to the IL-1 mediated diseases, NOMID and DIRA. Results A 4-year-old girl of mixed ethnic background, presented with sterile osteomyelitis, and elevated acute phase reactants and harbored a 17.8 Kb deletion on the maternal LPIN2 allele, and a splice site mutation, p.R517H, that variably spliced out exons 10 and 11 on the paternal LPIN2 allele. She achieved long-lasting remission on IL-1 blockade with canakinumab. Compared to controls, monocytes and monocyte-derived M1-like macrophages in the Majeed, NOMID and DIRA patients had elevated caspase-1 activity and secreted IL-1β levels. In contrast, LPS stimulated monocyte-derived M2-like macrophages from the Majeed patient released higher levels of osteoclastogenic mediators (IL-8, IL-6, TNFα, CCL2, MIP-1α/β b, CXCL8 and CXCL1) compared to NOMID patients and healthy controls. Accelerated osteoclastogenesis in the Majeed patient was associated with higher NFATc1 levels, enhanced JNK/MAP kinase, and reduced Src kinase activation and partially responded to JNK inhibiton and IL-1 but not IL-6 blockade. Conclusions We report two novel compound heterozygous disease-causing mutations in LPIN2 in a US patient with Majeed syndrome. LPIN2 deficiency drives differentiation of pro-inflammatory M2-macrophages and enhances intrinsic osteoclastogenesis thus providing a model for the pathogenesis of sterile osteomyelitis which differentiates Majeed syndrome from other IL-1 mediated autoinflammatory diseases.