MHC Class II Transactivator is an in vivo regulator of osteoclast differentiation and bone homeostasis co-opted from adaptive immunity

The molecular networks controlling bone homeostasis are not fully understood. The common evolution of bone and adaptive immunity encourages to investigate shared regulatory circuits. MHC Class II Transactivator (CIITA) is a master transcriptional co-activator believed to be exclusively dedicated for antigen presentation. CIITA is expressed in osteoclast precursors,and its expression is accentuated in osteoporotic mice. We thus asked whether CIITA plays a role in bone biology. To this aim, we fully characterized the bone phenotype of two mouse models of CIITA overexpression, respectively systemic and restricted to the monocyteosteoclast lineage. Both CIITA overexpressing mouse models revealed severe spontaneous osteoporosis, as assessed by micro-CT and histomorphometry, associated with increased osteoclast numbers and enhanced in vivo bone resorption, while osteoblast numbers and invivo bone forming activity were unaffected. To understand the underlying cellular and molecular bases, we investigated ex vivo the differentiation of mutant bone marrowmonocytes into osteoclasts and immune effectors, as well as osteoclastogenic signalingpathways. CIITA-overexpressing monocytes differentiated normally into effector macrophages or dendritic cells, but showed enhanced osteoclastogenesis, while CIITAablation suppressed osteoclast differentiation. Increased c-fms and RANK signaling underlay enhanced osteoclast differentiation from CIITA-overexpressing precursors. Moreover, by extending selected phenotypic and cellular analyses to additional genetic mouse models,namely MHC Class II deficient mice, and a transgenic mouse line lacking a specific CIITA promoter and re-expressing CIITA in the thymus, we excluded MHC Class II expression andT cells from contributing to the observed skeletal phenotype. Altogether, our study providescompelling genetic evidence that CIITA, the molecular switch of antigen presentation, plays a novel, unexpected function in skeletal homeostasis, independent differentiation and bone resorption in vivo.