Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism.

Abstract

The human developmental disorder 3MC syndrome is characterized by skeletal deformities associated with a deficiency of the pattern recognition molecule collectin-11 (CL-11), yet the underlying molecular and cellular mechanisms remain unclear. Here, we demonstrate that CL-11 deletion alone does not cause bone abnormalities in mice; however, combined deficiencies involving CL-11 and complement components MASP-2 (lectin pathway), CFB, or C3 (alternative amplification pathway) lead to significant vertebral bone loss and spinal curvature by 12 weeks of age. Ex vivo osteoclast (OCL) differentiation from bone marrow-derived cells of these double-knockout (DKO) mice was markedly impaired, but differentiation capacity was substantially restored by supplementation with CL-11. Furthermore, CL-11 and membrane attack complex (C5b-9) deposition were co-localized to OCLs and their precursors in normal bone tissues from embryonic stages to adulthood. These findings identify CL-11 as a critical osteoclastogenesis and bone maintenance regulator in conjunction with complement system-mediated signalling pathways and highlight CL-11 as a potential therapeutic target in diseases involving dysregulated osteoclast function and bone remodelling. Significance statementOur research in mice provides new insights into how mutations in the immune surveillance molecule collectin-11 contribute to skeletal abnormalities in humans. Evidence from our study suggests that normal osteoclasts interact with collectin-11 and complement, and that the disruption of this cooperation results in impaired bone maintenance in adulthood. These findings not only advance our understanding of osteoclast function but also highlight the therapeutic potential of targeting collectin-11 in conditions associated with osteoclast dysfunction.