Fibulin-1 is required for bone formation and Bmp-2-mediated induction of Osterix.

The extracellular matrix protein Fibulin-1 (Fbln1) has been shown to be involved in numerous processes including cardiovascular and lung development. Here we have examined the role of Fbln1 in bone formation. Alizarin red staining of skulls from Fbln1-deficient mice showed reduced mineralization of both membranous and endochondral bones. MicroCT (µCT) analysis of the calvarial bones (i.e., frontal, parietal and interparietal bones collectively) indicated that bone volume in Fbln1 nulls at neonatal stage P0 were reduced by 22% (p=0.015). Similarly, Fbln1 null frontal bones showed a 16% (p=0.035) decrease in bone volume, with a reduction in the interfrontal bone, and a discontinuity in the leading edge of the frontal bone. To determine whether Fbln1 played a role in osteoblast differentiation during bone formation, qPCR was used to measure the effects of Fbln1 deficiency on the expression of Osterix (Osx), a transcription factor essential for osteoblast differentiation. This analysis demonstrated that Osx mRNA was significantly reduced in Fbln1-deficient calvarial bones at developmental stages E16.5 (p=0.049) and E17.5 (p=0.022). Furthermore, the ability of Bmp-2 to induce Osx expression was significantly diminished in Fbln1-deficient mouse embryo fibroblasts. Together, these findings indicate that Fbln1 is a new positive modulator of the formation of membranous bone and endochondral bone in the skull, acting as a positive regulator of Bmp signaling.

Plasma fibulin-1 is linked to restrictive filling of the left ventricle and to mortality in patients with aortic valve stenosis.

BACKGROUND: Plasma fibulin-1 levels have been associated with N-terminal pro-B-type natriuretic peptide levels and left atrial size and shown to be predictive of mortality in patients with diabetes. The mechanisms behind these connections are not fully understood but are probably related to its roles as an extracellular matrix protein in cardiovascular tissues. METHODS AND RESULTS: One hundred twenty-five patients with severe aortic stenosis who were scheduled for aortic valve replacement (AVR) were evaluated with preoperative echocardiography and their plasma fibulin-1 levels were determined with ELISA. The cohort was followed for a median of 4 years after AVR. Increased restrictive left ventricular (LV) filling pattern was observed with increased plasma fibulin-1 levels (2% versus 29% versus 24% in low, middle, and high plasma fibulin-1 tertile groups, P=0.004). Likewise, reduced longitudinal systolic LV function (6.6 ± 1.1 versus 6.1 ± 1.3 versus 5.7 ± 1.5 cm/s, P=0.05) and increased LV filling pressures was systolic velocity of the mitral annulus observed with increasing plasma fibulin-1 concentrations (ratio of early transmitral flow velocity to early diastolic flow velocity of the mitral annulus 13 ± 4 versus 15 ± 5 versus 16 ± 6 in the fibulin-1 tertile groups, P=0.04). CONCLUSIONS: In patients with symptomatic severe aortic stenosis undergoing AVR, plasma fibulin-1 is associated with restrictive filling of the LV, decreased longitudinal systolic function of the LV, and increased LV filling pressures. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrial.gov with Identifier: NCT00294775.