Abstract
Septins are known to play key roles in supporting cytoskeletal stability, vesicular transport, endo-/exocytosis, stabilizing cellular membranes and forming diffusion barriers. Their function in mammalian cells is poorly investigated. The osteoclast offers an interesting tool to investigate septins because all cellular activities septins were reported to be involved in are critical for osteoclasts. However, the existence of septins in osteoclasts has not even been reported. Here we show that the SEPT9 gene and Septin 9 (SEPT9) protein are expressed and synthesized during differentiation of human osteoclasts. Pharmacological stabilization of septin filaments dose dependently inhibits bone resorption of human osteoclasts in vitro suggesting a role for septins in bone resorption. Attesting to this, conditional deletion of Sept9 in mice leads to elevated levels of trabecular bone and diminished femoral growth in vivo. Finally, systematic interrogation of the spatial organization of SEPT9 by confocal microscopy reveals that SEPT9 is closely associated to the structures known to be critical for osteoclast activity. We propose that septins in general and SEPT9 in particular play a previously unappreciated role in osteoclastic bone resorption.
Highlights
Septins are a family of filamentous proteins that are considered as the fourth component of the cytoskeleton, joining the other three well characterized cytoskeletal components: actin, microtubules and intermediate filaments[1]
Among the septins expressed in mammalian cells, Septin 9 (SEPT9) is interesting because it bridges the interaction between the cytoskeleton, membranes etc. to the septin octamers[7,16,17,19,21]
Mutations in septins are known to play a role in cancer and mutations in the SEPT9 gene can cause hereditary neuralgic amyotrophy[16,17,18]
Summary
Septins are a family of filamentous proteins that are considered as the fourth component of the cytoskeleton, joining the other three well characterized cytoskeletal components: actin, microtubules and intermediate filaments[1]. SEPT9 in particular is not well understood in the human setting, but it has been suggested to be a tumor suppressor as well as a proto-oncogene[16] and mutations in the SEPT9 gene have been shown to cause hereditary neuralgic amyotrophy[17] due to loss of proper hetero-octamer formation with other septins[18], disruption of proper microtubule bundling[19] and impaired vesicular transport[11]. An OC resorbing bone requires an efficient coordination between exo-and endocytosis and it occurs with high fidelity[25] This may require diffusion barriers at the level of the ruffled border to facilitate a separation of these two processes, but it requires an efficient and fast transport along microtubules and actin filaments, a function often ascribed to septins.
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