OGFRL1 deficiency causes CRMO via pathological osteoclastogenesis, with therapeutic response to TNF inhibitor

Objectives To verify the pathogenesis of the OGFRL1 loss‐of‐function variant (c.30del, p. F10Ffs*110) identified in a CRMO patient and investigate the underlying mechanism. Methods Whole exome sequencing and Sanger sequencing were performed to identify and confirm the variant. qPCR, ELISA, CBA, bulk RNA sequencing and single‐cell RNA sequencing were conducted to detect the inflammatory signatures of the patient versus healthy controls. Collagen antibody‐induced arthritis model was generated in Ogfrl1 knockout (KO) and wild‐type (WT) mice and micro‐CT 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 upregulated MAPK and NF‐κB signaling pathways, along with overproduction of proinflammatory 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 collagen antibody‐induced arthritis (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 versus WT mice. The patient responded well to TNF inhibitor therapy, with normalization of CRP, ESR, and SAA, and IL‐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.