Latent TGF-beta 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)-beta is abundantly present in bone tissue where it regulates osteoblast and osteoclast functions in a complex manner. Latent TGF-beta binding protein (LTBP)-1 mediates the extracellular matrix (ECM) targeting and accumulation of most TGF-beta in the bone. We describe here an important regulatory role for LTBP-3 in TGF-beta 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-beta activation. These changes coincided with the matrix maturation phase of osteogenic differentiation. The mechanism of LTBP-3 is most likely via TGF-beta activation in the early proliferative phase of the differentiation process. Later, when TGF-beta activity would inhibit further maturation and mineralization, LTBP-3 expression becomes downregulated and LTBP-1 containing large latent TGF-beta1 complexes accumulate into the ECM. These complexes represent readily available targets for osteoclast mediated release and activation of TGF-beta in bone tissue. Our results provide evidence that LTBP isoforms can differentially regulate TGF-beta activation and ECM accumulation during osteogenic differentiation.
Koli
Katri
K
Departments of Virology and Pathology, Haartman Institute and Helsinki University Hospital, University of Helsinki, Helsinki, Finland. katri.koli@helsinki.fi
Ryynänen
Merja J
MJ
Keski-Oja
Jorma
J
D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology
C509032:LTBP1 protein, human; C509038:LTBP3 protein, human; D053779:Latent TGF-beta Binding Proteins; D016212:Transforming Growth Factor beta