| Transforming growth factor βs (TGF-β) are multipotent regulators of cell growth, immune function and extracellar matrix (ECM) formation. TGF-βs are secreted from most cells as large latent complexes containing latent TGF-β binding protein (LTBP), TGF-β and its propeptide. LTBPs share similar domain structures with ECM microfibrillar proteins, the fibrillins. LTBPs and fibrillins are composed of multiple epidermal growth factor (EGF)-like repeats and cysteine-rich (CR) domains. LTBPs are proposed to be ECM structural proteins and/or regulators of TGF-β bioavailability in the ECM. However, the exact roles of LTBPs remain unclear.; We used in vivo and in vitro methods to study the biological functions of the 3rd member of the LTBP family - LTBP-3. Ltbp-3 null mice were generated. These mice display an abnormal skull shape around day 10 after birth due to premature ossification of the synchondroses at the base of the skull. By 6–9 months of age, the mutant mice display osteosclerosis and osteoporosis. Our hypothesis is that the lack of Ltbp-3 causes a decrease in active TGF-β, as the bone remodeling defects resemble those of transgenic mouse models with an impaired TGF-β signaling pathway. Ltbp-3 null mice in a 129 SvEv pure genetic background display defects in lung septation and some mutant mice show involution of the thymus and spleen. The thymus and spleen defect is caused by an elevation of serum corticosterone levels resulting from stress and probably is secondary to the lung defect. In in vitro studies, LTBP-3 is found to require the association of TGF-β for secretion. By studying the secretion of truncated LTBP-3 and LTBP-3/LTBP-1 chimeras, I mapped the long stretch of EGF-like repeats, the CR3 region and the most C-terminus EGF-like repeat as the regions in LTBP-3 that hinder its secretion. |
