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 have 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.