OGFRL1 Deficiency Causes Chronic Recurrent Multifocal Osteomyelitis Via Pathologic Osteoclastogenesis, With...

Area of Science:

• Immunology
• Genetics
• Rheumatology

Background:

• Chronic Recurrent Multifocal Osteomyelitis (CRMO) is a rare autoinflammatory bone disorder.
• The genetic basis of CRMO is not fully understood, with limited identified causative variants.

Purpose of the Study:

• To investigate the role of a specific OGFRL1 loss-of-function variant in CRMO pathogenesis.
• To elucidate the underlying molecular mechanisms contributing to CRMO in patients with OGFRL1 deficiency.

Main Methods:

• Whole exome and Sanger sequencing to identify and confirm the OGFRL1 variant.
• Analysis of inflammatory signatures using qPCR, ELISA, CBA, and RNA sequencing (bulk and single-cell).
• Collagen antibody-induced arthritis (CAIA) model in Ogfrl1 knockout mice and in vitro osteoclast differentiation assays.

Main Results:

• The patient exhibited activated inflammatory pathways (MAPK, NF-κB) and cytokine overproduction.
• Ogfrl1 knockout mice showed exacerbated arthritis, bone erosion, and enhanced osteoclast differentiation.
• The patient demonstrated a positive response to TNF inhibitor therapy, with reduced inflammatory markers and improved bone lesions.

Conclusions:

• OGFRL1 deficiency is identified as a novel genetic cause of CRMO.
• OGFRL1 plays a crucial role in suppressing inflammatory responses.
• This study offers new insights into CRMO pathogenesis and potential therapeutic strategies.