Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro

The Journal of Clinical Investigation
I R GarrettG R Mundy

Abstract

We have found that the ubiquitin-proteasome pathway exerts exquisite control of osteoblast differentiation and bone formation in vitro and in vivo in rodents. Structurally different inhibitors that bind to specific catalytic beta subunits of the 20S proteasome stimulated bone formation in bone organ cultures in concentrations as low as 10 nM. When administered systemically to mice, the proteasome inhibitors epoxomicin and proteasome inhibitor-1 increased bone volume and bone formation rates over 70% after only 5 days of treatment. Since the ubiquitin-proteasome pathway has been shown to modulate expression of the Drosophila homologue of the bone morphogenetic protein-2 and -4 (BMP-2 and BMP-4) genes, we examined the effects of noggin, an endogenous inhibitor of BMP-2 and BMP-4 on bone formation stimulated by these compounds and found that it was abrogated. These compounds increased BMP-2 but not BMP-4 or BMP-6 mRNA expression in osteoblastic cells, suggesting that BMP-2 was responsible for the observed bone formation that was inhibited by noggin. We show proteasome inhibitors regulate BMP-2 gene expression at least in part through inhibiting the proteolytic processing of Gli3 protein. Our results suggest that the ubiquitin-prot...Continue Reading

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Citations

Aug 21, 2007·Journal of Bone and Mineral Metabolism·Makoto HiraoHideki Yoshikawa
May 13, 2008·Journal of Bone and Mineral Metabolism·Riko NishimuraToshiyuki Yoneda
Jan 19, 2013·Cell Death & Disease·N SévèreP J Marie
Jul 25, 2007·Nature Reviews. Cancer·Teru HideshimaKenneth C Anderson
Mar 2, 2012·Nature Reviews. Drug Discovery·Kurt Redlich, Josef S Smolen
Sep 1, 2005·Prostate Cancer and Prostatic Diseases·P G WhangJ R Lieberman
Sep 1, 2007·The New England Journal of Medicine·Ernesto CanalisJohn P Bilezikian
Jan 1, 2004·The Journal of Biological Chemistry·Ming ZhaoDi Chen
Aug 1, 2007·Journal of Biomolecular Structure & Dynamics·Sreedhara SangadalaBoojala Vijay B Reddy
Apr 20, 2007·Molecular Biology of the Cell·Atsuko ShimoyamaToshiyuki Yoneda
Sep 17, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Marci D JonesJane B Lian
May 4, 2006·The Journal of Clinical Investigation·Venkatesh KrishnanOrmond A Macdougald
Jan 26, 2008·The Journal of Clinical Investigation·Siddhartha MukherjeeDavid T Scadden
Jan 26, 2008·The Journal of Clinical Investigation·G David Roodman
Aug 9, 2008·Blood·Joseph J PinzoneJohn D Shaughnessy
Apr 9, 2010·The Journal of Clinical Endocrinology and Metabolism·Ernesto Canalis
Apr 10, 2008·Journal of Cell Science·Mo ChenRegis J O'Keefe
Sep 19, 2007·International Journal of Hematology·Shuji OzakiToshio Matsumoto
Dec 30, 2009·Leukemia & Lymphoma·Shmuel Yaccoby
Mar 5, 2016·Expert Opinion on Investigational Drugs·Michail E KlontzasEleftherios Tsiridis
Nov 13, 2007·Hematology/oncology Clinics of North America·Constantine S MitsiadesKenneth C Anderson
Nov 13, 2007·Hematology/oncology Clinics of North America·Suzanne LentzschG David Roodman

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