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Over 200 million people suffer from osteoporosis worldwide, one third of which will develop osteoporotic bone fractures. Unfortunately, no effective cure exists. Mutations in plastin 3 (PLS3), an F-actin binding and bundling protein, cause X-linked primary osteoporosis in men and predisposition to osteoporosis in postmenopausal women. Moreover, the strongest association so far for osteoporosis in elderly women after menopause was connected to a rare SNP in PLS3, indicating a possible role of PLS3 in complex osteoporosis as well. Interestingly, 5% of the general population are overexpressing PLS3, with yet unknown consequences.Here, we studied ubiquitous Pls3 knockout and PLS3 overexpression in mice and demonstrate that both conditions influence bone remodeling and structure: While Pls3 knockout mice exhibit osteoporosis, PLS3 overexpressing mice show thickening of cortical bone and increased bone strength. We show that unbalanced PLS3 levels affect osteoclast development and function, by misregulating the NFκB pathway. We found upregulation of RELA (NFκB subunit p65) in PLS3 overexpressing mice - known to stimulate osteoclastogenesis - but strikingly reduced osteoclast resorption. We identify NFκB repressing factor (NKRF), as a novel PLS3 interactor, which increasingly translocates to the nucleus when PLS3 is overexpressed. We show that NKRF binds to the NFκB downstream target and master regulator of osteoclastogenesis Nfatc1, thereby reducing its transcription and suppressing osteoclast function. We found the opposite in Pls3 knockout osteoclasts, where decreased nuclear NKRF augmented Nfatc1 transcription, causing osteoporosis. Regulation of osteoclastogenesis and bone remodeling via the PLS3-NKRF-NFκB-NFATC1 axis unveils a novel possibility to counteract osteoporosis.
|Zeitschrift||Human molecular genetics|
|Publikationsstatus||Veröffentlicht - 10.09.2018|
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- 1 Laufend
DFG - Aufklärung neuer Pathomechanismen von Knochen- und Knorpelerkrankungen
Niehoff, A. & Wirth, B.
01.06.19 → 30.06.23
Projekt: Finanziert durch Drittmittel