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

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), CFB, or C3 (alternative pathway amplification) result in marked 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 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 (iPSC) lines. CL-11 and the membrane attack complex (MAC, C5b-9) co-localized 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 signalling, and they nominate CL-11 as a potential therapeutic target in conditions involving dysregulated osteoclast function and bone remodelling.