Profilin 1 Negatively Regulates Osteoclast Migration in Postnatal Skeletal Growth, Remodeling, and Homeostasis in Mice.

Shuhei Kajikawa, Jumpei Shirakawa, Ralph T Bottcher, Mercedes Costell, Yayoi Izu, Tadayoshi Hayata, Masaki Noda, Yoichi Ezura.

Profilin 1 (Pfn1), a regulator of actin polymerization, controls cell movement in a context-dependent manner. Pfn1 supports the locomotion of most adherent cells by assisting actin-filament elongation, as has been shown in skeletal progenitor cells in our previous study. However, because Pfn1 has also been known to inhibit migration of certain cells, including T cells, by suppressing branched-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 that Pfn1-knockdown (KD) enhances bone resorption in preosteoclastic RAW264.7 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 conditional Pfn1-deficient mice (Pfn1-cKO) by CathepsinK-Cre driver demonstrated postnatal skeletal phenotype, including dwarfism, craniofacial deformities, and long-bone metaphyseal osteolytic expansion, by 8 weeks of age. Metaphyseal and diaphyseal femurs were drastically expanded with suppressed trabecular bone mass as indicated by μCT analysis. Histologically, TRAP-positive osteoclasts were increased at endosteal metaphysis to diaphysis of Pfn1-cKO mice. The enhanced movement of Pfn1-cKO osteoclasts in culture was associated with a slight increase in cell size and podosome belt length, as well as an increase in bone-resorbing activity. Our study, for the first time, demonstrated that Pfn1 has critical roles in inhibiting osteoclast motility and bone resorption, thereby contributing to essential roles in postnatal skeletal homeostasis. Our study also provides novel insight into understanding skeletal deformities in human disorders.

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