title: Rib fractures and death from deletion of osteoblast βcatenin in adult mice is rescued by corticosteroids.
abstract: Ribs are primarily made of cortical bone and are necessary for chest expansion and ventilation. Rib fractures represent the most common type of non-traumatic fractures in the elderly yet few studies have focused on the biology of rib fragility. Here, we show that deletion of βcatenin in Col1a2 expressing osteoblasts of adult mice leads to aggressive osteoclastogenesis with increased serum levels of the osteoclastogenic cytokine RANKL, extensive rib resorption, multiple spontaneous rib fractures and chest wall deformities. Within days of osteoblast specific βcatenin deletion, animals die from respiratory failure with a vanishing rib cage that is unable to sustain ventilation. Increased bone resorption is also observed in the vertebrae and femur. Treatment with the bisphosphonate pamidronate delayed but did not prevent death or associated rib fractures. In contrast, administration of the glucocorticoid dexamethasone decreased serum RANKL and slowed osteoclastogenesis. Dexamethasone preserved rib structure, prevented respiratory compromise and strikingly increased survival. Our findings provide a novel model of accelerated osteoclastogenesis, where deletion of osteoblast βcatenin in adults leads to rapid development of destructive rib fractures. We demonstrate the role of βcatenin dependent mechanisms in rib fractures and suggest that glucocorticoids, by suppressing RANKL, may have a role in treating bone loss due to aggressive osteoclastogenesis.
authors: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors: JinZhu
authors: J
authors: Duan
authors: Yueh
authors: Y
authors: Lee
authors: Corey
authors: C
authors: Jania
authors: Jucheng
authors: J
authors: Gong
authors: Mauricio
authors: M
authors: Rojas
authors: Laurel
authors: L
authors: Burk
authors: Monte
authors: M
authors: Willis
authors: Jonathon
authors: J
authors: Homeister
authors: Stephen
authors: S
authors: Tilley
authors: Janet
authors: J
authors: Rubin
authors: Arjun
authors: A
authors: Deb
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000818:Animals; D003907:Dexamethasone / Q000627:therapeutic use; D007150:Immunohistochemistry; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D012253:Rib Fractures / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D051176:beta Catenin; D003907:Dexamethasone
references: J Pathol. 2007 May;212(1):47-55
references: 17370327
references: Nat Med. 2011 Sep 11;17(10):1235-41
references: 21909103
references: Arthritis Rheum. 2006 May;54(5):1463-72
references: 16646024
references: Science. 2000 Aug 11;289(5481):950-3
references: 10937998
references: J Clin Invest. 2008 Oct;118(10):3279-90
references: 18802478
references: Endocr Rev. 2008 Apr;29(2):155-92
references: 18057140
references: Bone. 2006 May;38(5):652-61
references: 16298558
references: Am J Physiol Lung Cell Mol Physiol. 2006 Aug;291(2):L144-56
references: 16473862
references: N Engl J Med. 2011 Jul 7;365(1):62-70
references: 21732837
references: J Bone Miner Res. 2010 Jul;25(7):1468-86
references: 20533309
references: Leukemia. 2009 Mar;23(3):435-41
references: 19039321
references: Dev Cell. 2005 May;8(5):727-38
references: 15866163
references: Development. 2005 Jan;132(1):49-60
references: 15576404
references: Nat Rev Clin Oncol. 2010 Nov;7(11):641-51
references: 20808302
references: J Trauma. 2010 Dec;69(6):1473-80
references: 21150526
references: Eur Cytokine Netw. 1998 Dec;9(4):655-61
references: 9889410
references: J Osteoporos. 2011;2011:457591
references: 22028986
references: Arthritis Rheum. 2012 May;64(5):1540-50
references: 22139865
references: Dev Cell. 2005 May;8(5):739-50
references: 15866164
references: J Biol Chem. 2006 Aug 18;281(33):23698-711
references: 16790443
references: J Biol Chem. 2012 Aug 24;287(35):29851-60
references: 22782898
references: PLoS One. 2012;7(4):e35965
references: 22558284
references: Exp Mol Med. 2002 May 31;34(2):145-51
references: 12085990
references: Dev Cell. 2005 May;8(5):751-64
references: 15866165
references: Nat Med. 2011 Sep 11;17(10):1231-4
references: 21909105
references: Endocrinology. 2005 Aug;146(8):3235-43
references: 15845617
references: Am J Pathol. 2002 May;160(5):1609-17
references: 12000713
references: J Cell Biochem. 2010 Jun 1;110(3):545-53
references: 20512915
references: Phys Med Biol. 2009 Apr 21;54(8):2323-40
references: 19321922
references: BMJ. 2010 Mar 15;340:c1069
references: 20231246
references: N Engl J Med. 2012 May 31;366(22):2048-51
references: 22571168
references: Ann Rheum Dis. 2011 Nov;70(11):2022-8
references: 21742639
references: Development. 2001 Apr;128(8):1253-64
references: 11262227
references: Ann Rheum Dis. 2004 Apr;63(4):354-9
references: 15020327