Collectin-11 regulates osteoclastogenesis and bone maintenance via a complement-dependent mechanism
Abstract
The human developmental disorder 3MC syndrome (Malpuech, Michels, Mingarelli, and Carnevale) features skeletal deformities associated with a deficiency of the pattern recognition molecule collectin-11 (CL-11), yet the underlying molecular and cellular mechanisms remain uncertain. Here, we demonstrate that CL-11 deletion alone does not produce skeletal abnormalities in mice; however, combined deficiencies of CL-11 with complement components MASP-2 (lectin pathway), complement factors B, or C3 (alternative pathway amplification) result in marked vertebral bone loss and spinal curvature by 12 wk of age. Ex vivo osteoclast (OCL) differentiation from bone marrow–derived cells of these double-knockout mice was profoundly impaired but was substantially restored by CL-11 supplementation. This dependence on CL-11 and complement was recapitulated in human OCLs derived from induced pluripotent stem cell lines. CL-11 and the membrane attack complex (C5b-9) colocalized to OCLs and their precursors in normal bone from embryonic development through to adulthood. Together, these findings identify CL-11 as a key regulator of osteoclastogenesis and bone homeostasis acting in concert with complement-mediated signaling, and they nominate CL-11 as a potential therapeutic target in conditions involving dysregulated osteoclast function and bone remodeling.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Mark C. Howard
Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London
Conrad A. Farrar
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College
Christopher L. Nauser
Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London
Yusun Jeon
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College
Anastasia Polycarpou
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College
Dorota Smolarek
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College
Roseanna Greenlaw
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College
Martyn Foster
Experimental Pathology Consultancy
Peter Garred
Consultant Laboratory of Molecular Medicine, Department of Clinical Immunology Section 7631, Rigshospitalet, University of Copenhagen
Daniela A. Vizitiu
Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London
Subhankar Mukhopadhyay
Medical Research Council Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London
Steven H. Sacks
Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College