The Cutaneous Microfibrillar Apparatus Contains Latent Transforming Growth Factor-β Binding Protein-1 (LTBP-1) and is a Repository for Latent TGF-β1

Abstract

The transforming growth factors-beta1 and beta2 (TGF-beta) stimulate synthesis of extracellular matrix proteins in vitro and appear upregulated in fibrotic conditions, in scar formation, and in wound healing. The extracellular matrix in turn might also act as a scavenger or repository for TGF-beta. We therefore studied the in situ distribution of latent TGF binding protein-1 (LTBP-1) and latent TGF-beta1 on extracellular matrix elements of normal human skin and skin regenerating from cultured keratinocyte autografts. We localized both LTBP-1 and latent TGF-beta1 to fibrillin-containing (elastic) microfibrils. Both LTBP-1 and latent TGF-beta1 were already present during the earliest stages of the de novo formation of the microfibrillar apparatus, i.e., on fusiform, randomly oriented microfibrils that later coalesced to form the typical candelabra-like structures in the papillary dermis. We show herewith that LTBP-1 exerts a dual role as a component of fibrillin-microfibrils of the skin and in targeting latent TGF-beta1 to the cutaneous microfibrillar apparatus. Thus, this major connective tissue structure does not only serve as a force bearing element and scaffold for elastin deposition in the dermis, but also as an important repository for latent TGF-beta in the skin.

Expression and Matrix Deposition of Latent Transforming Growth Factor β Binding Proteins in Normal and Fibrotic Rat Liver and Transdifferentiating Hepatic Stellate Cells in Culture

“…It has been shown in nonhepatic tissues that LTBP, a member of the fibrillin family of structural proteins, 46,23 can act as a component of connective tissue. 23,47,48 Thus, LTBP production by HSC/MFB might also be relevant for liver fibrogenesis by contributing this molecule to the formation of fibrotic matrix.…”

Assembly of fibrillin microfibrils governs extracellular deposition of latent TGFβ

“…LTBP-1 is probably not a structural component of microfibrils (Isogai et al, 2003;Cain et al, 2006), although LTBP-1 tissue distribution overlaps with, but is not identical to, that of fibrillin-1 (Raghunath et al, 1998;Dallas et al, 2000;Sinha et al, 2002;Isogai et al, 2003). The C-terminal region of LTBP-1 can interact with a four-domain N-terminal fibrillin-1 region, and with N-terminal fibrillin-2 with lower affinity, whereas fibulin-4 can inhibit the interaction of C-terminal LTBP-1 with fibrillin-1 (Isogai et al, 2003;Ono et al, 2009).…”

Tissue elasticity and the ageing elastic fibre

“…LTBPs appear to fulfil dual roles as both structural components of the ECM (Dallas et al 1995) and as TGFβ trafficking molecules (Miyazono et al 1991). Furthermore, the association of LTBPs with fibrillin microfibrils (Raghunath et al 1998;Unsold et al 2001) and the perturbations of normal TGFβ signalling in FBN1-mutant mice led to the hypothesis that fibrillin microfibrils play a major role in maintaining tissue homeostasis via LTBP-mediated sequestration of TGFβ (Denton and Abraham 2001;Neptune et al 2003). Fibulins are small ECM glycoproteins which appear to play important roles during development and wound healing (for a review see Chu and Tsuda 2004).…”