Plasma fibronectin contributes to adipose tissue extracellular matrix, affects adipocyte differentiation and insulin sensitivity of normal adipose tissue
Mahdokht Mahmoodi1, Mathieu Ferron 2, Jingjing Li3, Monzur Murshed M1,3,4,Mari T.Kaartinen1,5
1Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada 2 Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Canada 3 Department of Medicine, McGill University, Montreal, Canada 4 Shriners Hospital for Children, Montreal, QC, Canada 5 Centre for Bone and Periodontal Research, McGill University, Montreal, Canada
Osteoporosis is a bone metabolic disease characterized by loss of bone mass and increased fracture rates. The etiology of osteoporosis is multifactorial, and it can be caused by genetics, nutrition, medication, ageing-related changes and affects both sexes. At the cellular level, osteoporosis results from imbalanced activity between bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts) which are responsible for bone renewal and maintenance of bone quality. Both osteoblast and osteoclast differentiation and activities can be regulated by extracellular matrix (ECM) proteins. The liver regulates bone health and mass through circulating hepatokines and growth factors. Fibronectin (FN) is a multifunctional ECM glycoprotein that exists in two forms of cellular and plasma fibronectin (pFN). pFN is synthesized by hepatocytes in the liver and it is estimated that 90% of bone FN is pFN. It has been demonstrated that pFN affects osteoblastogenesis and osteoclastogenesis in vitro and bone matrix-mineral ratio in vivo. To analyze the role of pFN in remodeling of ageing male and female mice, we have created a pFN knockout model by breeding Fn1flx/flx and Alb-Cre driver mice resulting in a liver-specific conditional FN knockout (pFN KO) for skeletal phenotyping. Micro Computed Tomography (mCT) analysis of the tibial trabecular bone microarchitecture of 6-month-old mice showed a significant reduction in Bone Volume, BV/TV (p=0.0004), increase in trabecular spacing (Tb.Sp.) (p=0.0072), and decrease in trabecular number (Tb.N.) (p=0001) in male mice. Biomechanical strength of femurs via 3-point bending test was not changed. Cortical thickness was not altered. Measurement of bone resorption (CTX-1) and formation markers (P1NP) showed a significant reduction in male pFN KO mice, but not in females. Both female and male pFN KO mice showed a significant decrease in bone resorption. Histomorphometric analysis of bone cell numbers in vertebrae bone samples demonstrated a trend towards decrease for both osteoclasts and osteoblasts(both Cells per Trabecular Area and Cells per Bone Perimeter). Circulating osteocalcin (OCN) levels (total OCN) and its carboxylation status (Gla13-OCN and 3xGlu-OCN), as markers for bone formation and resorption, respectively were assessed by ELISA. No differences were found in males or females. Our study suggests that pFN may be an essential regulator of bone mass and both axes of bone remodeling.