Isoform of Fibronectin Mediates Bone Loss in Patients With Primary Biliary Cirrhosis by Suppressing Bone Formation

Abstract

Osteoporosis is a major cause of morbidity and decreased quality of life in patients with chronic cholestatic liver disease. It is established that this osteoporosis results from decreased bone formation, but the mechanisms for the interaction between liver and bone remain elusive. The aim of this study was to test the hypothesis that an increase in the production of cellular fibronectins during liver disease may result in decreased osteoblast-mediated mineralization and thus explain the decrease in bone formation. We performed a prospective cross-sectional study in patients with primary biliary cirrhosis and matched controls, followed by experiments on human and mouse osteoblasts in culture and injections in mice in vivo. In patients with primary biliary cirrhosis, the oncofetal domain of fibronectin correlated significantly with the decrease in osteocalcin, a marker of bone formation (r = -0.57, p < 0.05). In vitro, amniotic fluid fibronectin (aFN) containing mainly the oncofetal domain and EIIIA domain resulted in decreased osteoblast-mediated mineralization in human osteoblasts (69% decrease at 100 microg/ml; p < 0.01) and mouse osteoblasts (71% decrease; p < 0.05). Removing the EIIIA domain from aFN similarly suppressed mineralization by osteoblasts (78% decrease; p < 0.05). Injection of labeled aFN in mice showed that it infiltrates the bone, and its administration over 10 days resulted in decreased trabecular BMD (17% drop; p < 0.05), mineralizing surface (30% drop; p < 0.005), and number of osteoblasts (45% drop; p < 0.05). Increased production of a fibronectin isoform containing the oncofetal domain and its release in the circulation in patients with primary biliary cirrhosis is at least partially responsible for the decrease in bone formation seen in these patients. This establishes that a molecule that has thus far been viewed as an extracellular matrix protein exerts hormone-like actions.

Inhibition of fibronectin deposition improves experimental liver fibrosis

“…In vitro experiments in HSCs were performed on cells isolated from wild type mice or transgenic mice whose HSCs either do not produce fibronectin (FN À/À ) or produce a mutated fibronectin, able to form short fibrils but unable to activate RGD-binding integrins (because of the presence of an RGD-to-RGE mutation) (FN À/RGE ) [15,19,20]. Wild type C57BL/6 mice (Charles-River) were used for injection of pUR4 and CT-peptides.…”

Fibronectin inhibits osteoclastogenesis while enhancing osteoclast activity via nitric oxide and interleukin‐1β‐mediated signaling pathways

“…Induction of Mx was performed as described [Sakai et al, 2001]. Success of the deletion was confirmed by measuring the level of plasma FN by ELISA as previously described [Kawelke et al, 2008].…”

Blood Clot Formation Does Not Affect Metastasis Formation or Tumor Growth in a Murine Model of Breast Cancer

“…Primary cancellous bone was defined as the 120 µm band below the growth plate. Cancellous bone was defined as the remaining trabecular area that extends down 2 mm [21]. The same sections were used for dynamic and static histomorphometry, and data obtained from evaluation of the cancellous bone area defined above are presented.…”