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Analysis of the expression pattern of the latent transforming growth factor β binding protein isoforms in normal and diseased human liver reveals a new splice variant missing the proteinase‐sensitive hinge region

Latent transforming growth factor β binding protein (LTBP), a component of the extracellular matrix (ECM) of various tissues, is important for the secretion of TGF‐β and, furthermore, for the storage of TGF‐β in ECM. The proteolytic cleavage of LTBP is assumed to be the prerequisite for the activation of TGF‐β. We investigated the mRNA expression pattern of the three LTBP isoforms (LTBP‐1, ‐2, ‐3) and the protein distribution of the components of the large latent TGF‐β complex, namely LTBP‐1 and ‐2, latency‐associated protein (LAP), and TGF‐β, in human liver using reverse‐transcription polymerase chain reaction (RT‐PCR) and immunhistochemical alkaline phosphatase anti‐alkaline phosphatase (APAAP) staining. Parts of explanted livers diagnosed as hepatitis B, hepatitis C, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) and normal liver tissue were examined. LTBP transcripts were detected in the same manner in all liver specimens. Interestingly, we found a new splice variant of LTBP‐1 (LTBP‐1D), in which the sequence coding for the proteinase‐sensitive hinge region is deleted. The corresponding parts of the human LTBP‐2 and LTBP‐3 cDNA coding for the hinge region were sequenced and show neither similar proteinase cleavage sites nor deleted cDNA sequences. The proposed proteinase cleavage site of mouse LTBP‐3 seems not to be conserved in the human LTBP‐3 gene. By immunohistochemistry, LTBP‐1, ‐2, and LAP were detectable in normal and diseased livers and showed a different staining pattern for both LTBP isoforms. By contrast, TGF‐β showed a spotted staining pattern in diseased livers only, predominantly in the area of parenchymal cells that are close to fibrotic tissue. This strongly suggests the release of active TGF‐β from preexisting latent complexes. The LTBP‐1D splice variant, which is probably less sensitive against proteolytic degradation and therefore may protect TGF‐β from activation, may have importance for modulating the biological activity of TGF‐β in normal and diseased liver.