Abstract
Profilin 1 (Pfn1), a regulator of actin polymerization, controls cell movement in a context-dependent manner. Pfn1 supports thelocomotion of most adherent cells by assisting actin-filament elongation, as has been shown in skeletal progenitor cells in ourprevious study. However, because Pfn1 has also been known to inhibit migration of certain cells, including T cells, by suppressingbranched-end elongation of actin filaments, we hypothesized that its roles in osteoclasts may be different from that of osteoblasts.By investigating the osteoclasts in culture, we first verified thatPfn1-knockdown (KD) enhances bone resorption in preosteoclasticRAW264.7 cells, despite having a comparable number and size of osteoclasts.Pfn1-KD in bone marrow cells showed similar results.Mechanistically,Pfn1-KD osteoclasts appeared more mobile than in controls. In vivo, the osteoclast-specific conditionalPfn1-deficient mice (Pfn1-cKO) by CathepsinK-Cre driver demonstrated postnatal skeletal phenotype, including dwarfism, craniofacialdeformities, and long-bone metaphyseal osteolytic expansion, by 8 weeks of age. Metaphyseal and diaphyseal femurs weredrastically expanded with suppressed trabecular bone mass as indicated bymCT analysis. Histologically, TRAP-positive osteoclastswere increased at endosteal metaphysis to diaphysis ofPfn1-cKO mice. The enhanced movement ofPfn1-cKO osteoclasts in culturewas associated with a slight increase in cell size and podosome belt length, as well as an increase in bone-resorbing activity. Ourstudy, for the first time, demonstrated thatPfn1has critical roles in inhibiting osteoclast motility and bone resorption, therebycontributing to essential roles in postnatal skeletal homeostasis. Our study also provides novel insight into understanding skeletaldeformities in human disorders. © 2018 American Society for Bone and Mineral Research.
