OGFRL1 Deficiency Causes Chronic Recurrent Multifocal Osteomyelitis Via Pathologic Osteoclastogenesis, With Therapeutic Response to Tumor Necrosis Factor Inhibitor

OBJECTIVE: To verify the pathogenesis of the opioid growth factor receptor like-1 (OGFRL1) loss-of-function variant (c.30del, p. F10Ffs*110) identified in a patient with chronic recurrent multifocal osteomyelitis (CRMO) and to investigate the underlying mechanism. METHODS: Whole exome sequencing and Sanger sequencing were performed to identify and confirm the variant. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, cytometric bead assay, bulk RNA sequencing, and single-cell RNA sequencing were conducted to detect the inflammatory signatures of the patient versus healthy controls. A collagen antibody-induced arthritis (CAIA) model was generated in Ogfrl1 knockout (KO) and wild type (WT) mice, and micro-computed tomography scan was performed to investigate the pathogenicity of Ogfrl1 deficiency. In addition, osteoclast induction and differentiation in vitro was exerted to explore the underlying mechanism of Ogfrl1 deficiency. RESULTS: The patient exhibited up-regulated mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, along with overproduction of pro-inflammatory cytokines. Compared to healthy controls, apparent activation of myeloid cells was observed, especially in monocytes, dendritic cells, and low-density granulocytes (LDGs) of the patient. In the CAIA model, Ogfrl1 KO mice developed more severe and persistent arthritis and bone erosion than WT mice. Ogfrl1 KO mice were more prone to osteoclast differentiation than WT mice. The patient responded well to tumor necrosis factor inhibitor therapy, with normalization of C-reactive protein levels, erythrocyte sedimentation rate, serum amyloid A levels, and interleukin-6 levels, as well as improvement in osteolytic lesions. CONCLUSION: This study identified OGFRL1 deficiency as a novel cause of CRMO, highlighted the previously unrecognized role of OGFRL1 in restraining inflammatory responses, and provided novel insights into the pathogenesis and treatment of this autoinflammatory disorder.