Increased bone mass, altered trabecular architecture and modified growth plate organization in the growing skeleton of SOCS2 deficient mice

• Published in: Journal of cellular physiology Vol. 218; no. 2; pp. 276 - 284
• Main Authors: MacRae, V.E., Horvat, S., Pells, S.C., Dale, H., Collinson, R.S., Pitsillides, A.A., Ahmed, S.F., Farquharson, C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2009
• Subjects: Animals; Animals, Newborn; Biomarkers - metabolism; Bone Development - drug effects; Bone Resorption - metabolism; Cell Proliferation - drug effects; Cells, Cultured; Chondrocytes - cytology; Chondrocytes - drug effects; Chondrocytes - metabolism; Cytokines - pharmacology; Female; Gene Expression Regulation; Growth Plate - cytology; Growth Plate - drug effects; Growth Plate - metabolism; Inflammation Mediators - pharmacology; Metatarsal Bones - cytology; Mice; Organ Size - drug effects; Osteogenesis - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Suppressor of Cytokine Signaling Proteins - deficiency; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Tibia - drug effects; Tibia - growth & development; Tibia - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.21593

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.