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Increased bone mass, altered trabecular architecture and modified growth plate organization in the growing skeleton of SOCS2 deficient mice
Author(s) -
MacRae V.E.,
Horvat S.,
Pells S.C.,
Dale H.,
Collinson R.S.,
Pitsillides A.A.,
Ahmed S.F.,
Farquharson C.
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21593
Subject(s) - socs2 , medicine , endocrinology , endochondral ossification , cytokine , chemistry , biology , cartilage , anatomy , suppressor , cancer
Suppressor of cytokine signalling‐2 (SOCS2) negatively regulates the signal transduction of several cytokines. Socs2 −/− mice show increased longitudinal skeletal growth associated with deregulated GH/IGF‐1 signalling. The present study examined the role of SOCS2 in endochondral ossification and trabecular and cortical bone formation, and investigated whether pro‐inflammatory cytokines associated with pediatric chronic inflammatory disorders mediate their effects through SOCS2. Seven‐week‐old Socs2 −/− mice were heavier (27%; P < 0.001) and longer (6%; P < 0.001) than wild‐type mice. Socs2 −/− tibiae were longer (8%; P < 0.001) and broader (18%; P < 0.001) than that of wild‐type mice, and the Socs2 −/− mice had wider growth plates (24%; P < 0.001) with wider proliferative and hypertrophic zones (10% ( P < 0.05) and 14% ( P < 0.001) respectively). Socs2 −/− mice showed increased total cross‐sectional bone area (16%: P < 0.001), coupled to increased total tissue area (17%; P < 0.05) compared to tibia from wild‐type mice. Socs2 −/− mice showed increased percent bone volume (101%; P < 0.001), trabecular number (82%; P < 0.001) and trabecular thickness (11%; P < 0.001), with associated decreases in trabecular separation (19%; P < 0.001). TNFα exposure to growth plate chondrocytes for 48 h increased SOCS2 protein expression. Growth of metatarsals from 1‐day‐old Socs2 −/− and Socs2 +/+ mice, as well as expression of Aggrecan , Collagen Type II and Collagen Type X , were inhibited by TNFα, with no effect of genotype. Our data indicate that physiological levels of SOCS2 negatively regulate bone formation and endochondral growth. Our results further suggest that pro‐inflammatory cytokines mediate their inhibitory effects on longitudinal bone growth through a mechanism that is independent of SOCS2. J. Cell. Physiol. 218: 276–284, 2009. © 2008 Wiley‐Liss, Inc.