Exercise-stimulated primary cilia on preosteoclasts promote periosteal-bone formation

Exercise profoundly impacts cortical bones that are refractory to current drugs. However, the mechanisms underlying these changes remain unclear. Here we show that mechanosensitive primary cilia on myeloid-lineage preosteoclasts play a critical role in mediating exercise-induced periosteal bone formation. We crossed Cx3cr1-Cre or Ctsk-Cre mice with Ift88 ^loxP/loxP and/or Kif3a ^loxP/loxP mice to create models that lack primary cilia on myeloid-lineage cells at various stages of osteoclastic differentiation. On exercise, all these mice displayed decreases in periosteal bone formation and cortical bone size. Mechanical stimulation of primary cilia on preosteoclasts activated Dvl2, suppressing Cathepsin K production and preventing periostin degradation. The resulting elevation of periostin levels promoted periosteal bone formation. Notably, Cathepsin K inhibition overcame the effects of primary cilia deficiency in exercised Cx3cr1-Cre;Ift88 ^loxP/loxP mice, restoring cortical bone size, bone formation, and periosteal periostin levels to those observed in exercised Ift88 ^loxP/loxP littermates. By uncovering the primary cilia-preosteoclast-Ctsk-periostin axis, this study provides a foundation for developing targeted therapies to enhance cortical bone strength.