Latent TGF-β binding proteins (LTBPs)-1 and -3 coordinate proliferation and osteogenic differentiation of human mesenchymal stem cells

Mesenchymal stem cells (MSCs) possess the capability to differentiate into bone forming cells, osteoblasts, and thus represent a new therapeutic tool in regenerative medicine. Transforming growth factor (TGF)-β is abundantly present in bone tissue where it regulates osteoblast and osteoclast functions in a complex manner. Latent TGF-β binding protein (LTBP)-1 mediates the extracellular matrix (ECM) targeting and accumulation of most TGF-β in the bone. We describe here an important regulatory role for LTBP-3 in TGF-β activation and autocrine growth control in MSCs. LTBP-3 knockdown via siRNA mediated silencing resulted in reduced cell proliferation and reduced osteogenic differentiation. When MSCs were induced to undergo differentiation, LTBP-3 levels became downregulated in parallel with reduced TGF-β activation. These changes coincided with the matrix maturation phase of osteogenic differentiation. The mechanism of LTBP-3 is most likely via TGF-β activation in the early proliferative phase of the differentiation process. Later, when TGF-β activity would inhibit further maturation and mineralization, LTBP-3 expression becomes downregulated and LTBP-1 containing large latent TGF-β1 complexes accumulate into the ECM. These complexes represent readily available targets for osteoclast mediated release and activation of TGF-β in bone tissue. Our results provide evidence that LTBP isoforms can differentially regulate TGF-β activation and ECM accumulation during osteogenic differentiation.