PIDDosome deficiency impairs bone remodeling by increasing osteoclast ploidy and function.

Osteoporosis is a chronic disease driven by an imbalance between bone-building osteoblasts and bone-resorbing osteoclasts, whose hyperactivation can promote this condition. Osteoclasts are multinucleated cells, and their activity directly correlates with their ploidy level. Multinucleation associates with the accumulation of extra centrosomes that can activate the PIDDosome pathway. Depending on cell type, this can lead to a p53/p21-mediated cell cycle arrest, or BCL2-regulated apoptosis. Here, we report that the PIDDosome controls polyploidization in osteoclasts and its absence triggers bone erosion in mice. PIDDosome activation in osteoclasts depends on the presence of extra centrosomes bearing the distal appendage protein ANKRD26. Consistently, loss of Ankrd26 phenocopies PIDDosome-deficiency in osteoclasts. Surprisingly, p53 and p21, which restrict cell cycle progression in the presence of extra centrosomes, are not involved in limiting osteoclast polyploidization and function. In support of this notion, bones from p53-/- mice display a higher trabecular bone mass phenotype, and osteoclasts generated from p21-/- mice show normal OC ploidy and function. Altogether, we document that the PIDDosome regulates bone homeostasis by regulating osteoclast polyploidization and their bone-resorbing function independently of the canonical p53/p21 axis, hinting towards unknown downstream effectors. We propose that modulation of PIDDosome activation might be therapeutically exploited for osteoporosis treatment, while its inhibition may ameliorate osteopetrosis symptoms.