ECTS2013 Oral Communications Osteoblasts and osteocytes (6 abstracts)
Severe osteopenia, increased bone marrow adipogenesis, and fibronectin matrix changes in mice lacking both TG2 and FXIIIA transglutaminases
Aisha Mousa 1 , Cui Cui 1 , Aimei Song 1 , Vamsee Myneni 1 , Jingjing Li 1 , Gerry Melino 2 , Gerhard Dickneite 3 , Monzur Murshed 1 & Mari Kaartinen 1
1McGill University, Montreal, Quebec, Canada; 2University of Leicester, Leicester, UK; 3CSL Behring GmbH, Marburg, Germany.
Osteoblasts produce protein-crosslinking enzymes, transglutaminase 2 (TG2) and factor XIIIA (FXIIIA), which regulate fibronectin matrix stabilization and osteoblast differentiation in vitro. To examine if they are important in bone remodeling and in maintenance of bone quality and mass in vivo, we performed skeletal phenotyping of Tgm2−/− and F13a1−/− mice and generated a double-null Tgm2−/−;F13a1−/− mouse. Tgm2−/− mice showed no loss of bone mass and maintained normal bone mineral density (BMD) to 12 months age. F13a1−/− mice showed normal BMD values at 3 and 6 months, but significantly decreased BMD (−6.6%) at 12 months. Supportive of synergistic functions, the double-null Tgm2−/−;F13a1−/− mice were osteopenic at 3 months of age, showing a significant decrease in femur BMD (−16.3%). Three-point bending tests showed significantly decreased bone strength. Micro-computed tomography of the Tgm2−/−;F13a1−/− double-null mice showed significant alterations in trabecular bone parameters: decreased BV/TV (−57%), decreased Tr.N (−51%) and increased Tr.Sp (+49%). The fibronectin matrix from double-null bone showed significantly increased detergent solubility, suggesting defective matrix stabilization. Osteoblast number was significantly increased (N.Ob/B.Pm +35%); however, mineral apposition rate showed no difference suggesting enhanced cell proliferation but impaired differentiation of preosteoblasts and/or precursors in the double-null mice. Bone marrow adipocity showed large increases in both fat percent (+70.7%) and adipocyte numbers (+65%) suggesting that TG2 and FXIIIA might regulate an osteoblast-adipocyte switch via fibronectin matrix stabilization. The presence of an osteoblast differentiation defect was further supported by a significantly higher RANKL/OPG ratio, this likely causing the observed increases in osteoclast number (N.Ocl./B/Pm +104%) and the resorption marker (RatLaps; +80%) consistent with the bone loss observed in the double-null mice.
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Bone Abstracts
ISSN 2052-1219 (online)
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