Skip to main content

Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis


The extracellular matrix (ECM) plays a key role in tissue formation, homeostasis and repair, mutations in ECM components have catastrophic consequences for organ function and therefore, for the fitness and survival of the organism. Collagen, fibrillin and elastin polymers represent the architectural scaffolds that impart specific mechanic properties to tissues and organs. Fibrillin assemblies (microfibrils) have the additional function of distributing, concentrating and modulating local transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signals that regulate a plethora of cellular activities, including ECM formation and remodeling. Fibrillins also contain binding sites for integrin receptors, which induce adaptive responses to changes in the extracellular microenvironment by reorganizing the cytoskeleton, controlling gene expression, and releasing and activating matrix-bound latent TGF-β complexes. Genetic evidence has indicated that fibrillin-1 and fibrillin-2 contribute differently to the organization and structural properties of non-collagenous architectural scaffolds, which in turn translate into discrete regulatory outcomes of locally released TGF-β and BMP signals. Additionally, the study of congenital dysfunctions of fibrillin-1 has yielded insights into the pathogenesis of acquired connective tissue disorders of the connective tissue, such as scleroderma. On the one hand, mutations that affect the structure or expression of fibrillin-1 perturb microfibril biogenesis, stimulate improper latent TGF-β activation, and give rise to the pleiotropic manifestations in Marfan syndrome (MFS). On the other hand, mutations located around the integrin-binding site of fibrillin-1 perturb cell matrix interactions, architectural matrix assembly and extracellular distribution of latent TGF-β complexes, and lead to the highly restricted fibrotic phenotype of Stiff Skin syndrome. Understanding the molecular similarities and differences between congenital and acquired forms of skin fibrosis may therefore provide new therapeutic tools to mitigate or even prevent disease progression in scleroderma and perhaps other fibrotic conditions.


The extracellular matrix (ECM) is a highly heterogeneous amalgam of morphologically diverse architectural entities composed of collagenous or elastic polymers, adaptor proteins and hydrophilic proteoglycans. The architectural matrix organizes and imparts structural integrity to individual tissues, in addition to modulating cell behavior by interacting with cell surface receptors and soluble growth factors. Primary or secondary dysfunctions in components of the architectural matrix can therefore interfere with both tissue integrity and cell performance. Cases in point are the fibrillin assemblies (microfibrils and elastic fibers), which represent the non-collagenous scaffolds of the architectural matrix. The present review focuses on the biology and pathophysiology of fibrillin assemblies, with a particular emphasis on recent evidence connecting fibrillin-1 with the control of TGF-β signaling and tissue fibrosis.

Fibrillin assemblies and interactions

Fibrillins 1 and 2 are ubiquitous glycoproteins that self-polymerize into filamentous microfibrils with an average diameter of 10 nm in which individual molecules are organized in longitudinal head-to-tail arrays and associate laterally as well [14]. Fibrillin microfibrils can additionally serve as the structural template for tropoelastin deposition and/or crosslinking during elastic fiber formation. Specific segments of the fibrillins interact in vitro with numerous extracellular signaling and cell surface molecules, including fibronectin, fibulins, latent TGF-β-binding proteins (LTBPs), bone morphogenetic protein (BMP) pro-peptides, syndecans and integrins. The multiple molecular interactions of fibrillins are believed to drive the assembly of morphologically distinct macroaggregates, which contribute to imparting the structural integrity to individual tissues and organs (structural role), and to target TGF-β and BMP complexes to the architectural matrix, which contributes to instructing the behavior of cells (instructive role) TGF-βs and BMPs are potent modulators of ECM metabolism, that are under the control of a complex network of relays and servomechanisms operating within and outside the cell, and at the cell surface [57]. Extracellular control of local TGF-β and BMP signals - and -in particular the one that involves fibrillin microfibrils [3] - has recently emerged as a critical aspect of tissue formation, homeostasis and repair [6]. There is however, significant variability in how fibrillins can bind TGF-β and BMP complexes, and how fibrillin-bound TGF-β and BMP complexes can signal to cells.

TGF-β 1, 2 and 3 (hereafter collectively referred to as TGF-β) are secreted either as a small latent complex (SLC) in which bioactive homodimers are non-covalently associated with processed pro-peptides (latency-associated protein; LAP) or as a large latent complex (LLC) in which the TGF-β-SLC complex is bound to LTBPs [8]. Association with LAP blocks the ability of bioactive TGF-β dimers to interact with the cognate receptors TGFBR1 and TGFBR2, whereas binding to LTBPs directs TGF-β-SLC sequestration in the ECM through LTBP-mediated association with fibronectin fibrils first, and fibrillin assemblies subsequently [9, 10]. Matrix metalloproteinases (MMPs), BMP1, thrombospondin-1, small proteoglycans and integrin receptors are involved in releasing latent TGF-β from the ECM by modifying LLC structure or disrupting LAP-mediated latency [11]. Thus, latent TGF-β complexes bind indirectly to extracellular microfibrils and as a result, fibrillin-bound TGF-β-LLC requires a two-step activation process to signal; i.e.: release from the ECM and LAP dissociation.

BMPs are also secreted and targeted to the ECM as crosslinked dimers non-covalently associated with the pro-peptides that can interact in vitro with the N-termini of fibrillin-1 and -2 [12, 13]. In contrast to TGF-β, however, BMP pro-peptides do not generally confer latency to the associated dimers, and as a result, BMPs can readily signal once released from the ECM [14]. Accordingly, the fibrillins act as storage scaffolds that distribute, concentrate and confer latency to BMPs, while soluble antagonists and their modulators are probably the only extracellular molecules that control the activity matrix-unbound (free) BMPs. Hence, BMP complexes bind directly to extracellular microfibrils, and signaling by fibrillin-bound BMPs solely involves the step of releasing the ligand from the matrix.

Fibrillins 1 and 2 share an Arg-Gly-Asp (RGD) sequence within a flexible loop in the middle of the molecules, which favors binding to integrins α5β1 and αvβ3/6[1518]; additionally, the N-terminal third of fibrillin-2 contains a second RGD sequence [2]. An in vitro model of platelet-derived growth factor-induced fibroblast migration suggests that the common RGD sequence of fibrillins induces more lamellipodia and more widespread remodeling of the leading edge, whereas the unique RGD motif of fibrillin-2 stimulates migration with greater directional persistence [19]. Additionally, evidence indicates that a high affinity heparin-binding site located immediately next to the RGD site of fibrillin-1 enhances integrin-mediated cell adhesion, probably by binding syndecan receptors [20]. There is reason to believe that the interactions between fibrillins and cell receptors and between fibrillin and fibronectin fibrils occur in the pericellular space, where they probably guide both the early steps of fibrillin polymerization and the targeting of growth factors to extracellular microfibrils [9, 10, 2126]. Integrins αvβ5/6/8 can also participate in latent TGF-β release from the matrix and/or activation through proteolytic and non-proteolytic mechanisms [2729]. Thus, pericellular release of ECM remodeling signals appears to be locally integrated with microfibril biogenesis and growth factor targeting to the matrix.

Fibrillin diseases in humans

Heterozygous mutations in fibrillin-1 or fibrillin-2 cause two clinically related disorders of the connective tissue, MFS (OMIM 154700) and congenital contractural arachnodactyly (CCA: OMIM 121050) respectively [30, 31]. MFS is predominantly characterized by abnormalities in the ocular, skeletal and cardiovascular systems. Deficiencies in the cardiovascular system, particularly development of aortic root dilatation, are the main cause of mortality and morbidity in affected patients [30]. The main clinical features of CCA include joint contractures, crumpled ears and musculoskeletal manifestations; cardiovascular and gastrointestinal anomalies are occasionally present in infants with a severe/lethal form of the disease [31]. On the one hand, the multiple traits of MFS and CCA underscore the importance of fibrillin-1 and fibrillin-2 microfibrils in the formation and function of several organ systems. On the other hand, the distinct phenotypes of MFS and CCA imply that fibrillin-1 and -2 have discrete functions in spite of participating in the same architectural assemblies. The functional diversity of fibrillins -1 and -2 involves both their structural contribution to microfibril integrity, as the two proteins display temporally distinct expression patterns, and their instructive contribution to cell performance, as loss of function mutant mice show discrete tissue-specific TGF-β and/or BMP-dependent abnormalities (see below) [32].

Mutations in the human fibrillin-1 gene (FBN1) are particularly interesting because they are associated with a wide spectrum of clinical severity in MFS, irrespective of where they are located in the protein or how much they reduce gene expression [30]. This apparent lack of genotype-phenotype correlations also applies to the occasional FBN1 mutations in patients who do not fulfill the strict diagnostic criteria of MFS [33]; these rare instances include familial ectopia lentis (OMIM 129600), Shprintzen-Goldberg syndrome (OMIM 182212) and Weill-Marchesani syndrome (OMIM 608328) [3436]. By contrast, there is a very strong correlation between mutations affecting a specific domain of fibrillin-1 and the unique phenotype of stiff skin syndrome (SSS; OMIM 184900) [37]. SSS mutations cluster around the sole integrin-binding RGD sequence of fibrillin-1, and lead to a highly restricted (as opposed to a systemic) phenotype that resembles a congenital form of scleroderma. The domain-specific nature and unique phenotypic outcome of SSS mutations suggests a different pathogenetic mechanism from that of MFS. Clinical and pathogenetic relationships between SSS and scleroderma are discussed more extensively in the last section of this review.

Fibrillin mutations in mice

Several mice with mutations in the Fbn1 or Fbn2 gene have been created that replicate the clinical features of MFS, SSS and CCA. Mutations in Fbn1 include those that blunt gene expression and lead in homozygosity to progressively severe (Fbn1mgR/mgR mice) or neonatal lethal MFS (Fbn1-/- mice) and those that perturb protein structure and lead in heterozygosity lead to mild (Fbn1C1039G/+ mice) or subclinical MFS (Fbn1GT-8/+ mice) [3841]. Loss of fibrillin-2 synthesis in Fbn2-/- mice is associated with several CCA traits, such as joint contractures, osteopenia and muscle weakness and atrophy, as well as a unique limb patterning defect not seen in either CCA patients or Fbn1-/- mice, namely digit fusion (syndactyly) with involvement of either soft or hard tissue [42]. Lastly, a spontaneous tandem duplication within Fbn1 is responsible for the phenotype of tight skin (Tsk/+) mice, which includes myocardial, skeletal and pulmonary abnormalities of MFS and fibrotic features of SSS (see below) [43].

Characterization of mice harboring mutations in Fbn1 and/or Fbn2 has provided invaluable insights into microfibril biogenesis and function. The first insight indicated that fibrillins -1 and -2 perform partially overlapping structural functions in developing and mature tissue. This conclusion is based on the findings that Fbn2 expression is largely restricted to the forming and remodeling tissues, that fibrillin-2 proteins are buried within postnatal microfibrils, and that the vascular phenotype and average survival of Fbn1-/- ;Fbn2-/- or Fbn1-/- ;Fbn2-/+ mice are significantly more severe than those of Fbn1-/- or Fbn2-/- mice, [40, 42, 44, 45]. Taken together, these data imply that fibrillin-2 polymers form the inner scaffold that supports the deposition and/or organization of fibrillin-1 polymers, and that continued and proper deposition of fibrillin-1 is absolutely required for the postnatal maturation and mechanical compliance of aortic tissue.

The second insight that has emerged from the studies of Fbn mutant mice is that the organization of fibrillin-1 and fibrillin-2 polymers within the forming and mature microfibrils also determines the contextual regulation of local TGF-β and BMP signals. Vascular and bone findings support this contention. Aortic aneurysm progression in Fbn1C1039G/+ and Fbn1mgR/mgR mice is largely driven by increased latent TGF-β activation and signaling secondary to loss of TGF-β-LLC sequestration in the ECM (Figure 1), a molecular phenotype that is replicated in cultured primary smooth muscle cell isolated from Fbn1 mutant aortas [46, 47]. By contrast, improper TGF-β signaling is not seen in either the aortas or cultured vascular smooth muscle cells from Fbn2-/- mice [40, 47]. Hence, fibrillin-1, but not fibrillin-2, restricts TGF-β activity in the medial layer of the postnatal aorta by interacting with LTBP components of the LLC. Likewise, the unique presence of syndactyly in Fbn2-/- mice and its apparent association with decreased BMP signaling are strong indications that fibrillin-2, but not fibrillin-1, promotes BMP activity in the developing autopods [42]. Bone remodeling is yet another example of a tissue-specific program in which fibrillin -1 and -2 contribute differently to the extracellular regulation of local TGF-β and BMP signals [4850]. Both Fbn1-/- and Fbn2-/- osteoblast cultures display enhanced TGF-β signaling, which inhibits osteoblast maturation, but only cultured osteoblasts from Fbn1-/- and Fbn1mgR/mgR mice exhibit higher than normal BMP activity, which promotes osteoblast maturation [48, 49]. As a result, osteoblasts deficient for fibrillin-2 fail to mature properly, and bone formation is impaired in Fbn2-/- mice, whereas osteoblast maturation and bone formation are largely unaffected in Fbn1-/- and Fbn1mgR/mgR mice [48, 49]. Increased TGF-β signaling, however, upregulates Rankl production by osteoblasts, with consequent stimulation of bone resorption by osteoclasts in mice deficient in either fibrillin-1 or fibrillin-2 deficient mice [49, 50]. Collectively, these genetic findings indicate that microfibrils regulate local TGF-β and BMP signals in a manner that is stage-, tissue-, ligand- and fibrillin-specific. The mechanistic basis for this specificity contextual remains to be determined.

Figure 1
figure 1

Hypothetical models of MFS and SSS pathogenesis. The top drawing depicts the normal wild-type (WT) condition in which a cell interacts with fibrillin-1 microfibrils through RGD-mediated integrin binding and through TGF-β signals released from the fibrillin-1 microfibrils (thin arrows). Mutations in MFS decrease microfibril deposition/stability and promote excessive TGF-β signaling (thick arrow). Mutations in stiff skin syndrome perturb integrin-mediated microfibril deposition and increase matrix-directed TGF-β signaling (thick arrows).

Fibrillin-1 and scleroderma

Tissue fibrosis is traditionally viewed as the pathological counterpart of physiological wound healing [51]. In response to insult(s) altering ECM integrity or architecture, activated mesenchymal cells initiate a matrix-remodeling program in which anabolic and catabolic activities are tightly balanced. In fibrotic conditions, such as scleroderma, cell insensitivity to normal regulatory signals leads to excessive ECM deposition and ultimately, organ failure [51, 52]. Past efforts have mostly focused on characterizing the molecular mechanisms responsible for aberrant cell behavior and less attention has been paid to defining the extracellular determinants of tissue fibrosis. This situation has rapidly changed because new evidence from acquired and congenital forms of human scleroderma and Tsk/+ mice has implicated dysfunction of fibrillin-1 microfibrils in skin fibrosis [53].

Widespread tissue fibrosis is the hallmark of systemic sclerosis (SSc), the most common form of acquired scleroderma [54, 55]. Thickening and hardening of the skin is progressive, and evolves from the extremities to the trunk in a centripetal manner that rarely affects the back. In contrast to other fibrotic disorders, autoimmunity and vasculopathy characteristically precede SSc fibrosis [56, 57]. Skin fibrosis begins near to blood vessels in the reticular dermis, and is accompanied by a prominent inflammatory infiltrate [5860]. Fibroblasts explanted from involved sites show a transiently activated phenotype characterized by elevated expression of ECM components, MMP inhibitors (TIMPs) and adhesion molecules, in addition to constitutive TGF-β signaling [51]. Consistent with this last finding, SSc biopsies display increased activation of the Smad2/3 pathway, and skin fibrosis is observed in transgenic mice over-expressing constitutively active TGFBR1 [61, 62]. There is also evidence suggesting that perivascular monocellular infiltrate may be responsible for exaggerated TGF-β activity, and that activated SSc fibroblasts may themselves augment TGF-β signaling by increasing TGFBR expression [63, 64]. Alteration of LLC storage in the ECM may also promote the increase in TGF-β signaling as well. Indeed, SSc fibroblasts secrete and assemble microfibrils that appear to be unstable, and SSc biopsies exhibit disorganized fibrillin-1 aggregates and fragmented elastic fibers throughout the dermis [6567]. Moreover, FBN1 polymorphisms characterize high SSc incidence in Choctaw Indians and a smaller cohort of Japanese patients [68, 69]. Lastly, circulating autoantibodies against fibrillin-1 have been described in SSc patients, that can induce the molecular signature of activated cells in healthy fibroblasts, apparently through a TGF-β-dependent mechanism [70].

As already mentioned, Tsk/+ mice replicate some MFS features (bone lengthening, cardiac hypertrophy and lung emphysema) as well as characteristic SSc features (skin fibrosis with excessive accumulation of collagen I and microfibrils, and the emergence of circulating autoantibodies against topoisomerase I, RNA polymerase I and fibrillin-1) [7174]. Additional pathological correlates between the human and mouse phenotypes include the ability of TGF-β interference to reduce skin thickness, either genetically by pairing the Tsk allele with Tgfβ haploinsufficiency or pharmacological inhibition of Smad3-mediated transcription in Tsk/+ mice [75, 76]. Furthermore, expression of the Tsk protein in mouse embryonic fibroblasts is accompanied by excessive collagen I deposition along with up-regulation of the microfibril-associated protein MAPG2, which is over-expressed in SSc skin [77, 78]. There are also key differences between the two phenotypes. First, Tsk+ mice lack the microvascular involvement characteristic of SSc [79]; second, fibrosis is still apparent in immunodeficient Tsk/+ mice [80]; and third, the circulating autoantibodies in Tsk/+ mice emerge relatively late compared with the onset of skin fibrosis [71]. Moreover, the fibrotic involvement in Tsk/+ mice follows a different pattern from that in SSc, as skin thickening begins after 2-4 weeks, progresses slowly and is more evident in the interscapular area and is absent from regions devoid of fascia, such as the ear pinna [81, 82]. Lastly, histological analyses have confirmed the relative normalcy of dermal thickness and collagen content in Tsk/+ skin, in addition to attributing the fibrotic phenotype to a marked hyperplasia of the loose subdermal connective tissue, which results in increased tethering of the skin to the underlying muscle layer [81].

The discovery of FBN1 mutations in SSS has provided a more cogent argument for the causal relationship between altered microfibril biogenesis, increased TGF-β signaling, and skin fibrosis [37]. SSS is an extremely rare congenital disease (~40 cases reported to date) that manifest in infancy or in early childhood with rock-hard skin bound firmly to the underlying tissues [83, 84]. Skin manifestations are most prominently observed in areas with abundant fascia, such as the buttocks, thighs, and shoulder girdle area. However, there is some disagreement about the specific area affected, sometimes being reported as the dermis and in a few cases as the underlying fascia [37, 8587]. It should also be noted that histological studies have rarely assessed hypodermal tissue because this examination requires more invasive procedures [85]. Early clinical presentation of SSS often impacts skeletal growth and results in deformities such as scoliosis, a tiptoe gait, and a narrow thorax that can ultimately impair pulmonary function and lead to respiratory distress [84, 88]. In most cases, the disease progresses slowly and is not fatal. Lack of visceral involvement, immunologic abnormalities and vascular disturbances differentiate this inherited condition from rare cases of pediatric SSc [84, 89].

In spite of the above considerations, there is reason to believe that elucidating the molecular underpinning of skin fibrosis in SSS patients and Tsk/+ mice could yield general principles of disease progression in SSc. SSS mutations cluster around the sole integrin (RGD)-binding site of fibrillin-1, whereas the Tsk mutation generates longer fibrillin-1 molecules with duplicated RGD sequences [37, 43]. Current evidence indicates that altered cell-matrix interactions in SSS have multiple negative effects on ECM assembly, TGF-β activity, cell identity and integrin signaling [37]. Specifically, perturbed integrin-directed fibrillin-1 assembly in SSS leads to excessive microfibril deposition and consequently, greater latent TGF-β concentration and signaling (Figure 1). Increased TGF-β activity in turn induces keratinocytes to lose their phenotype and become activated mesenchymal cells (epithelial to mesenchymal transition; EMT), an observation in line with keratinocyte contribution to hypertrophic scar formation [90]. Additionally, loss of RGD binding also perturbs microfibril-induced integrin signaling, that normally directs several cellular activities during skin development (Figure 1). The larger size of fibrillin-1 together with duplicated RGD sequences may trigger the same cascade of events in the skin of Tsk/+ mice, in addition to eventuating MFS-like manifestations in other organ systems by mechanism(s) that influence other aspects of fibrillin-1 assembly and function [43, 91, 92]. In line with this argument, the pathogenesis of reduced bone mass in Tsk/+ mice differs from that of Fbn1mgR/mgR mice, as impaired bone formation and increased bone resorption in the latter [49, 93]. The difference are likely to be accounted for by unopposed elevation of TGF-β signaling in Tsk/+ bones and by balanced augmentation of both TGF-β and BMP activity in the Fbn1mgR/mgR counterparts [49]. Further analyses of Tsk/+ mice and creation of SSS mice promises to elucidate the pathogenetic contribution of fibrillin-1 microfibrils to fibrotic phenotypes.

Conclusions and perspectives

Fibrillin assemblies represent a nodal point that integrates the biological network of structural and instructive information flowing to and from the cell, which orchestrates tissue formation, homeostasis and repair. Such an integrated view of the molecular interactions within fibrillin assemblies and between them and the resident cells has expanded our understanding of the roles of the architectural matrix substantially, in addition to providing new means to test evidence-based therapies in conditions characterized by primary or secondary defects in fibrillin assemblies. In this light, TGF-β immediately emerged as the first network component to be targeted by pharmacological interventions aimed at improving aortic aneurysm progression in MFS. The strategy was based on the prior knowledge that blockade of angiotensin II receptor I (AT1R) activity reduces excessive TGF-β signaling in experimental renal and cardiac fibrosis [94, 95]. within accordance with this prediction, losartan treatment was shown to restore aortic wall architecture in Fbn1C1039G/+ mice and to mitigate aortic root dilation in a small cohort of children with severe MFS [46, 96]. A more recent study has confirmed the efficacy of losartan treatment in improving aortic wall degeneration in Fbn1mgR/mgR mice, a more severe model of MFS than the Fbn1C1039G/+ mouse, even though the regimen showed no beneficial impact to counteract bone loss [49]. These findings, together with evidence suggesting that some individuals may not respond to losartan as effectively as others [97, 98], strongly argue for a multifaceted treatment strategy in MFS and perhaps, in related disorders of the connective tissue. Indeed, in vivo data have demonstrated that broad inhibition of tyrosinekinases is a more efficient strategy to control tissue fibrosis than using specific receptor inhibitors [99101]. Likewise, in vivo and ex vivo lines of evidence have implicated additional contributors to vascular disease onset and/or progression in MFS. First, studies of Fbn1-/- aortas and vascular SMC suggest that stress responses triggered by a structurally deficient matrix and mediated by ROS through the Ras/mitogen-acivated protein kinase signaling pathway participate in Smad2/3 activation independently of TGF-β [47]. Second, improved aortic wall architecture in Fbn1 mutant mice systemically treated with doxycycline implies that improper MMP activity (and conceivably TIMP activity as well) exacerbates TGFβ-driven aneurysm progression in MFS [102, 103]. Third, paradoxical increase of TGFβ signaling in the Loeys-Dietz syndrome (LDS; OMIM-609192), which is caused by heterozygous loss-of-function mutations in TGFBR1 or TGFBR2 [104], points to the potential impairment of TGFβ auto-regulation, compensatory mechanisms and/or alternative signaling cascades [30, 32]. Lastly, domain-specific mutations in SSS correlate perturbations in ECM assembly and cell-matrix communication with triggering a wide array of signals that stimulate and sustain fibrosis [37]. TGF-β and EMT antagonism on the one hand, and integrin agonism on the other, have therefore emerged as therapeutic strategies to be tested alone or in mutant mice that model human SSS [37].

Moreover, the recent report that lymphatic and blood endothelial cells participate in fibrillin-1 deposition in human skin raises the intriguing possibility of a microvascular origin of dermal fibrosis in SSS [105]. It is therefore safe to conclude that the study of SSS patients and mice will benefit our understanding of SSc pathogenesis, despite the noted differences in clinical presentation and natural history between these two diseases.



congenital contractural arachnodactyly


extracellular matrix


epithelial-to-mesenchymal transition

FBN and Fbn:

human and mouse fibrillin genes, respectively


latency associated protein


Loeys-Dietz syndrome


large latent complex


latent TGFβ-associated protein


Marfan syndrome


matrix metalloproteinase


Systemic Sclerosis


Stiff Skin syndrome


TGFβ receptor

Tsk :

tight skin mutation.


  1. Kielty CM, Sherratt JM, Marson A, Baldock C: Fibrillin microfibrils. Adv Protein Chem. 2005, 70: 405-436. full_text.

    Article  CAS  PubMed  Google Scholar 

  2. Hubmacher D, Tiedemann K, Reinhardt DP: Fibrillins: From biogenesis of microfibrils to signaling functions. Curr Top Dev Biol. 2006, 57: 93-122. full_text.

    Article  Google Scholar 

  3. Ramirez F, Rifkin DB: Extracellular microfibrils: contextual platforms for TGFβ and BMP signaling. Curr Opin Cell Biol. 2009, 21: 616-622. 10.1016/

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Ramirez F, Sakai LY: Biogenesis and function of fibrillin assemblies. Cell Tissue Res. 2010, 339: 71-82. 10.1007/s00441-009-0822-x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Shi Y, Massagué J: Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003, 63: 515-524.

    Google Scholar 

  6. ten Dijke P, Arthur HM: Extracellular control of TGFβ signaling in vascular development and disease. Nat Rev Mol Cell Biol. 2007, 8: 857-869. 10.1038/nrm2262.

    Article  CAS  PubMed  Google Scholar 

  7. Kang JS, Liu C, Derynck R: New regulatory mechanisms of TGF-β receptor function. Trends Cell Biol. 2009, 19: 385-394. 10.1016/j.tcb.2009.05.008.

    Article  CAS  PubMed  Google Scholar 

  8. Annes JP, Munger JS, Rifkin DB: Making sense of latent TGF-β activation. J Cell Sci. 2003, 116: 217-224. 10.1242/jcs.00229.

    Article  CAS  PubMed  Google Scholar 

  9. Dallas SL, Sivakumar P, Jones CJP, Chen Q, Peters DM, Mosher DF, Humphries MJ, Kielty CM: Fibronectin regulates latent transforming growth factor-β (TGFβ) by controlling matrix assembly of latent TGFβ binding protein-1. J Biol Chem. 2005, 280: 18871-18880. 10.1074/jbc.M410762200.

    Article  CAS  PubMed  Google Scholar 

  10. Sivakumar P, Czirok A, Rongish BJ, Wang YP, Dallas SL: New insights into extracellular matrix assembly and reorganization from dynamic imaging of extracellular matrix proteins in living osteoblasts. J Cell Sci. 2006, 1350-60. 10.1242/jcs.02830. 119

  11. Rifkin DB: Latent transforming growth factor-β TGF-β) binding proteins: orchestators of TGF-β availability. J Biol Chem. 2005, 280: 7409-7412. 10.1074/jbc.R400029200.

    Article  CAS  PubMed  Google Scholar 

  12. Katagiri T, Suda T, Miyazono K: The bone morphogenetic proteins. The TGF-β Family. Edited by: Derynck R, Miyazono K. 2008, Cold Spring Harbor Laboratory Press. Cold Spring Harbor, NY, 121-149.

    Google Scholar 

  13. Sengle G, Charbonneau NL, Ono RN, Sasaki T, Alvarez J, Keene DR, Bachinger HP, Sakai LY: Targeting of bone morphogenetic protein growth factor complexes to fibrillin. J Biol Chem. 2008, 283: 13874-13888. 10.1074/jbc.M707820200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Sengle G, Ono RN, Lyons KM, Bachinger HP, Sakai LY: A new model for growth factor activation: type II receptors compete with the prodomain for BMP-7. J Mol Biol. 2008, 381: 1025-1039. 10.1016/j.jmb.2008.06.074.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Sakamoto H, Broekelmann T, Cheresh DA, Ramirez F, Rosenbloom J, Mecham RP: Cell-type specific recognition of RGD- and non-RGD-containing cell binding domains in fibrillin-1. J Biol Chem. 1996, 271: 4916-4922. 10.1074/jbc.271.9.4916.

    Article  CAS  PubMed  Google Scholar 

  16. Pfaff M, Reinhardt DP, Sakai LY, Timpl R: Cell adheshion and integrin binding to recombinant fibrillin-1. FEBS Lett. 1996, 384: 247-250. 10.1016/0014-5793(96)00325-0.

    Article  CAS  PubMed  Google Scholar 

  17. Bax DV, Bernard SE, Lomas A, Morgan A, Humphries J, Shuttleworth CA, Humphries JJ, Kielty CM: Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by beta 1 and αv β 3 integrins. J Biol Chem. 2003, 278: 34605-34616. 10.1074/jbc.M303159200.

    Article  CAS  PubMed  Google Scholar 

  18. Jovanovic J, Takagi J, Choulier L, Abrescia NG, Stuart DI, van der Merwe PA, Mardon HJ, Handford PA: α5β6 is a novel receptor for human fibrillin-1: Comparative studies of molecular determinants underlying integrin-RGD affinity and specificity. J Biol Chem. 2007, 282: 6743-6751. 10.1074/jbc.M607008200.

    Article  CAS  PubMed  Google Scholar 

  19. McGowan SE, Holmes AJ, Mecham RP, Ritty TM: Arg-Gly-Asp-containing domains of fibrillin-1 and -2 distinctly regulate lung fibroblast migration. Am J Respir Cell Mol Biol. 2008, 38: 435-445. 10.1165/rcmb.2007-0281OC.

    Article  CAS  PubMed  Google Scholar 

  20. Bax DV, Mahalingam Y, Cain S, Mellody K, Freeman L, Younger K, Shuttleworth CA, Humphries MJ, Couchman JR, Kielty CM: Cell adheshion to fibrillin-1: Identification of an Arg-Gly-Asp-dependent synergy region and a heparin-binding site that regulates focal adheshion formation. J Cell Sci. 2007, 120: 1383-1392. 10.1242/jcs.003954.

    Article  CAS  PubMed  Google Scholar 

  21. Chen Q, Sivakumar P, Barley C, Peters DM, Gomes RR, Farach-Carson MC, Dallas SL: Potential role for heparan sulfate proteoglycans in regulation of transforming growth factor-β (TGF-β) by modulating assembly of latent TGF-β-binding protein-1. J Biol Chem. 2007, 282: 26418-26430. 10.1074/jbc.M703341200.

    Article  CAS  PubMed  Google Scholar 

  22. Hubmacher D, El-Hallous EL, Nelea V, Kaartinen MT, Lee ER, Reinhardt DP: Biogenesis of extracellular microfibrils: Multimerization of the fibrillin-1 C terminus into bead-like structures enables self assembly. Proc Natl Acad Sci USA. 2008, 105: 6548-6553. 10.1073/pnas.0706335105.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Cain SA, Baldwin A, Mahalingam Y, Raynal B, Jowitt TA, Shuttleworth CA, Couchman JR, Kielty CM: Heparan sulfate regulates fibrillin-1 and C-terminal interactions. J Biol Chem. 2008, 283: 27017-27027. 10.1074/jbc.M803373200.

    Article  CAS  PubMed  Google Scholar 

  24. Kinsey R, Williamson MR, Chaudhry S, Mellody KT, McGovern A, Takahashi S, Shuttleworth CA, Kielty CM: Fibrillin-1 microfibril deposition is dependent on fibronectin assembly. J Cell Sci. 2008, 2696-2704. 10.1242/jcs.029819. 121

  25. Sabatier L, Chen D, Fagotto-Kaufmann C, Hubmacher D, McKee MD, Annis DS, Mosher DF, Reinhardt DP: Fibrillin assembly requires fibronectin. Mol Biol Cell. 2009, 20: 846-858. 10.1091/mbc.E08-08-0830.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Massam-Wu T, Chiu M, Choudhury R, Chaudhry SS, Baldwin AK, McGovern A, Baldock C, Shuttleworth CA, Kielty CM: Assembly of fibrillin microfibrils governs extracellular deposition of latent TGF β. J Cell Sci. 2010, 3006-3016. 10.1242/jcs.073437. 123

  27. Mu DS, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL: The integrin α(v)β8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J Cell Biol. 2002, 493-507. 10.1083/jcb.200109100. 157

  28. Annes JP, Chen Y, Munger JS, Rifkin DB: Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J Cell Biol. 2004, 723-734. 10.1083/jcb.200312172. 165

  29. Wipff PJ, Rifkin DB, Meister JJ, Hinz B: Myofibroblast contraction activates latent TGF-β 1 from the extracellular matrix. J Cell Biol. 2007, 1311-1323. 10.1083/jcb.200704042. 179

  30. Ramirez F, Dietz HC: Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Cell Biol. 2007, 252-258. 17

  31. Godfrey M: Congenital Contractural Arachnodactyly. Gene Reviews. Edited by: Pagon RA, Bird TC, Dolan CR, Stephens K. 2007, Seattle University of Washington [Internet], updated

    Google Scholar 

  32. Ramirez F, Dietz HC: Extracellular microfibrils in vertebrate development and disease processes. J Biol Chem. 2009, 284: 14677-14681. 10.1074/jbc.R900004200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, DeBacker J, Devereux RB, Hillhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, DePaepe AM: The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010, 476-485. 10.1136/jmg.2009.072785. 47

  34. Kainulainen K, Karttunen L, Puhakka L, Sakai LY, Peltonen L: Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome. Nat Genet. 1994, 6: 64-69. 10.1038/ng0194-64.

    Article  CAS  PubMed  Google Scholar 

  35. Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC: Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet. 1996, 209-211. 10.1038/ng0296-209. 12

  36. Faivre L, Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, Le Merrer M, Collod-Beroud G, Boileau C, Munnich A, Cormier-Daire V: In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet. 2003, 40: 34-36. 10.1136/jmg.40.1.34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Loeys BL, Gerber EE, Riegert-Johnson D, Iqbal S, Whiteman P, McConnell V, Chillakuri CR, Macaya D, Coucke PJ, De Paepe A, Judge DP, Wigley F, Davis EC, Mardon HJ, Handford P, Keene DR, Sakai LY, Dietz HC: Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Science Transl Med. 2010, 2: 23ra20.

    Article  CAS  Google Scholar 

  38. Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T, Jensen Biery N, Dietz HC, Sakai LY, Ramirez F: Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA. 1999, 96: 3819-3823. 10.1073/pnas.96.7.3819.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC: Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest. 2004, 114: 172-181.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Carta L, Pereira L, Arteaga-Solis E, Lee-Arteaga SY, Lenart B, Starcher B, Merkel CA, Sukoyan M, Kerkis A, Hazeki N: Fibrillins 1 and 2 perform partially overlapping functions during aortic development. J Biol Chem. 2006, 281: 8016-8023. 10.1074/jbc.M511599200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Charbonneau NL, Carlson EJ, Tufa S, Sengle G, Manalo EC, Carlberg VM, Ramirez F, Keene DR, Sakai LY: In vivo studies of mutant fibrillin-1 microfibrils. J Biol Chem. 2010, 24943-24955. 10.1074/jbc.M110.130021. 285

  42. Arteaga-Solis E, Gayraud B, Lee SY, Shum L, Sakai L, Ramirez F: Regulation of limb patterning by extracellular microfibrils. J Cell Biol. 2001, 154: 275-281. 10.1083/jcb.200105046.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Siracusa LD, McGrath R, Ma Q, Moskow JJ, Manne J, Christner PJ, Buchberg AM, Jimenez SA: A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res. 1996, 6: 300-313. 10.1101/gr.6.4.300.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang H, Hu W, Ramirez F: Developmental expression of fibrillin genes suggest hetergeneity of extracellular microfibrils. J Cell Biol. 1995, 129: 1165-1176. 10.1083/jcb.129.4.1165.

    Article  CAS  PubMed  Google Scholar 

  45. Charbonneau NL, Jordan CD, Keene DR, Lee-Arteaga S, Dietz HC, Rifkin DB, Ramirez F, Sakai LY: Microfibril structure masks fibrillin-2 in postnatal tissues. J Biol Chem. 2010, 285: 20242-20251. 10.1074/jbc.M109.087031.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, Podowski M, Neptune ER, Halushka MK, Bedja D, Gabrielson K, Rifkin DB, Carta L, Ramirez F, Huso DL, Dietz HC: Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006, 312: 117-121. 10.1126/science.1124287.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Carta L, Smaldone S, Zilberberg L, Loch D, Dietz HC, Rifkin DB, Ramirez F: p38 MAPK is an early determinant of promiscuous Smad2/3 signaling in the aortas of fibrillin-1 (Fbn1)-null mice. J Biol Chem. 2009, 5630-5636. 284

  48. Nistala H, Lee-Arteaga S, Smaldone S, Siciliano G, Ono R, Sengle G, Arteaga-Solis E, Levasseur R, Ducy P, Sakai LY, Karsenty G, Ramirez F: Fibrillin-1 and -2 differentially modulate endogenous TGFβ and BMP bioavailability during bone formation. J Cell Biol. 2010, 190: 10.1083/jcb.201003089. in press

    Google Scholar 

  49. Nistala H, Lee-Arteaga S, Carta L, Cook JR, Smaldone S, Siciliano G, Rifkin A N, Dietz HC, Rifkin DB, Ramirez F: Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome. Human Mol Genet. 2010.

    Google Scholar 

  50. Nistala H, Lee-Arteaga S, Smaldone S, Siciliano G, Ramirez F: Extracellular microfibrils control osteoblast-supported osteoclastogenesis by restricting TGFβ stimulation of RANKL production. J Biol Chem. 2010, 285: 34126-34133. 10.1074/jbc.M110.125328.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Leask A, Abraham DJ: TGF-β signalling and the fibrotic response. FASEB J. 2004, 18: 816-822. 10.1096/fj.03-1273rev.

    Article  CAS  PubMed  Google Scholar 

  52. Gabrielli A, Avvedimento EV, Krieg T: Scleroderma. N Engl J Med. 2009, 1989-2003. 10.1056/NEJMra0806188. 360

  53. Avvedimento EV, Gabrielli A: Stiff and tight skin: a rear window into fibrosis without inflammation. Sci Transl Med. 2010, 2: 23ps13.

    Article  PubMed  Google Scholar 

  54. Rodnan GP, Lipinski E, Luksick J: Skin thickness and collagen content in progressive systemic sclerosis and localized scleroderma. Arthritis Rheum. 1979, 130-140. 10.1002/art.1780220205. 22

  55. Lovell CR, Nicholls AC, Duance VC, Bailey AJ: Characterization of dermal collagen in systemic sclerosis. Br J Dermatol. 1979, 359-369. 10.1111/j.1365-2133.1979.tb01635.x. 100

  56. Varga J, Abraham D: Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007, 117: 557-567. 10.1172/JCI31139.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Krieg T, Takehara K: Skin disease: a cardinal feature of systemic sclerosis. Rheumatology (Oxford). 2009, 48 (Suppl 3): iii14-18. 10.1093/rheumatology/kep108.

    Google Scholar 

  58. Fleischmajer R, Perlish JS, West WP: Ultrastructure of Cutaneous Cellular Infiltrates in Scleroderma. Arch Dermatol. 1977, 113: 1661-1666. 10.1001/archderm.113.12.1661.

    Article  CAS  PubMed  Google Scholar 

  59. Fleischmajer R, Gay S, Meigel WN, Perlish JS: Collagen in the cellular and fibrotic stages of scleroderma. Arthritis Rheum. 1978, 21: 418-428. 10.1002/art.1780210404.

    Article  CAS  PubMed  Google Scholar 

  60. Torres JE, Sanchez JL: Histopathologic differentiation between localized and systemic scleroderma. Am J Dermatopathol. 1998, 242-245. 10.1097/00000372-199806000-00003. 20

  61. Mori Y, Chen SJ, Varga J: Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum. 2003, 48: 1964-1978. 10.1002/art.11157.

    Article  CAS  PubMed  Google Scholar 

  62. Sonnylal S, Denton CP, Zheng B, Keene DR, He R, Adams HP, Vanpelt CS, Geng YJ, Deng JM, Behringer RR, de Combrugghe B: Postnatal induction of transforming growth factor β signalling in fibroblasts of mice recapitulates clinical, histologic, an biochemical features of scleroderma. Arthritis Rheum. 2007, 334-344. 10.1002/art.22328. 56

  63. Sfikakis PP, McCune BK, Tsokos M, Aroni K, Vayiopoulos G, Tsokos GC: Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis. Clin Immunol Immunopathol. 1993, 199-204. 10.1006/clin.1993.1170. 69

  64. Pannu J, Gore-Hyer E, Yamanaka M, Smith EA, Rubinchik S, Dong JY, Jablonska S, Blaszcyk M, Trojanowska M: An increased transforming growth factor-β receptor type I: type II ratio contributes to elevated collagen protein synthesis that is resistant to inhibition via a kinase-deficient transforming growth factor-β receptor type II in scleroderma. Arthritis Rheum. 2004, 1566-1577. 10.1002/art.20225. 50

  65. Fleischmajer R, Jacobs L, Schwartz E, Sakai LY: Extracellular microfibrils are increased in localized and systemic scleroderma skin. Lab Invest. 1991, 791-798. 64

  66. Quaglino D, Bergamini G, Boraldi F, Manzini E, Davidson JM, Pasquali Ronchetti I: Connective tissue in skin biopsies from patients suffering systemic sclerosis. J Submicrosc Cytol Pathol. 1996, 28: 287-296.

    PubMed  Google Scholar 

  67. Rustin MH, Papadaki L, Rode J: Elastic fibres in patients with systemic sclerosis. A morphological study. Virchows Arch A Pathol Anat Histopathol. 1989, 115-120. 10.1007/BF01606315. 416

  68. Tan FK, Stivers DN, Foster MW, Chakraborty R, Howard RF, Milewicz DM, Arnett FC: Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population. Arthritis Rheum. 1998, 41: 1729-1737. 10.1002/1529-0131(199810)41:10<1729::AID-ART5>3.0.CO;2-8.

    Article  CAS  PubMed  Google Scholar 

  69. Tan FK, Wang N, Kuwana M, Chakraborty R, Bona CA, Milewicz DM, Arnett FC: Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations. Arthritis Rheum. 2001, 44: 893-890. 10.1002/1529-0131(200104)44:4<893::AID-ANR146>3.0.CO;2-3.

    Article  CAS  PubMed  Google Scholar 

  70. Zhou X, Tan FK, Milewicz DM, Guo X, Bona CA, Arnett FC: Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-β pathway to recapitulate the 'scleroderma phenotype'. J Immunol. 2005, 175: 4555-4560.

    Article  CAS  PubMed  Google Scholar 

  71. Bocchieri MH, Henriksen PD, Kasturi KN, Muryoi T, Bona CA, Jimenez SA: Evidence for autoimmunity in the tight skin mouse model of systemic sclerosis. Arthritis Rheum. 1991, 599-605. 10.1002/art.1780340512. 34

  72. Greene MC, Sweet HO, Bunker LE: Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol. 1976, 82: 493-512.

    Google Scholar 

  73. Muryoi T, Kasturi KN, Kafina MJ, Saitoh Y, Usuba O, Perlish JS, Fleischmajer R, Bona CA: Self reactive repertoire of tight skin mouse: immunochemical and molecular characterization of anti-topoisomerase I autoantibodies. Autoimmunity. 1991, 9: 109-117. 10.3109/08916939109006746.

    Article  CAS  PubMed  Google Scholar 

  74. Murai C, Saito S, Kasturi KN, Bona CA: Spontaneous occurrence of anti-fibrillin-1 autoantibodies in tight-skin mice. Autoimmunity. 1998, 28: 151-155. 10.3109/08916939808996283.

    Article  CAS  PubMed  Google Scholar 

  75. McGaha T, Saito S, Phelps RG, Gordon R, Noben-Trauth N, Paul WE, Bona C: Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4R β and transforming growth factor-β genes. J Invest Dermatol. 2001, 116: 136-143. 10.1046/j.1523-1747.2001.00217.x.

    Article  CAS  PubMed  Google Scholar 

  76. Hasegawa M, Matsuhita Y, Horikawa M, Higashi K, Tomigahara Y, Kaneko H, Shirasaki F, Fujimoto M, Takehara K, Sato S: A Novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis. Arthritis Rheum. 2009, 60: 3465-3475. 10.1002/art.24934.

    Article  CAS  PubMed  Google Scholar 

  77. Lemaire R, Farina G, Kissin E, Shipley JM, Bona C, Korn JH, Lafyatis R: Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen. Arthritis Rheum. 2004, 915-926. 10.1002/art.20053. 50

  78. Lemaire R, Korn JH, Shipley JM, Shipley JM, Lafyatis R: Increased expression of type I collagen induced by microfibril-associated glycoprotein 2: novel mechanistic insights into the molecular basis of dermal fibrosis in scleroderma. Arthritis Rheum. 2005, 1812-1823. 10.1002/art.21059. 52

  79. Wick G, Christner PJ, Jiménez SA: Lack of endothelial cell apoptosis in the dermis of tight skin 1 and tight skin 2 mice. Arthritis Rheum. 1999, 581-584. 42

  80. Dodig TD, Mack KT, Cassarino DF, Clark SH: Development of the tight-skin phenotype in immune-deficient mice. Arthritis Rheum. 2001, 44: 723-727. 10.1002/1529-0131(200103)44:3<723::AID-ANR122>3.0.CO;2-V.

    Article  CAS  PubMed  Google Scholar 

  81. Baxter RM, Crowell TP, McCrann ME: Analysis of the tight skin (Tsk1/+) mouse as a model for testing antifibrotic agents. Lab Invest. 2005, 1199-1209. 10.1038/labinvest.3700331. 85

  82. Oble DA, Teh HS: Tight skin mouse subcutaneous hypertrophy can occur in the absence of αβ T cell receptor-bearing lymphocytes. J Rheumatol. 2001, 1852-1855. 28

  83. Esterly NB, McKusick VA: Stiff skin syndrome. Pediatrics. 1971, 47: 360-369.

    CAS  PubMed  Google Scholar 

  84. Liu T, McCalmont TH, Frieden IJ, Williams ML, Connolly MK, Gilliam AE: The stiff skin Syndrome: case series, differential diagnosis of the stiff skin phenotype and review of the literature. Arch Dermatol. 2008, 1351-1359. 10.1001/archderm.144.10.1351. 144

  85. Jablonska S, Schubert H, Kikuchi I: Congenital fascial dystrophy: stiff skin syndrome-a human counterpart of the tight-skin mouse. J Am Acad Dermatol. 1989, 21: 943-950. 10.1016/S0190-9622(89)70280-2.

    Article  CAS  PubMed  Google Scholar 

  86. Geng S, Lei X, Toyohara JP, Zhan P, Wang J, Tan S: Stiff skin syndrome. J Eur Acad Dermatol Venereol. 2006, 729-732. 10.1111/j.1468-3083.2006.01619.x. 20

  87. Guiducci S, Distler JH, Milia AF: Stiff skin syndrome: evidence for an inflammation-independent fibrosis?. Rheumatology (Oxford). 2009, 48: 849-852. 10.1093/rheumatology/kep118.

    Article  Google Scholar 

  88. Foti R, Leonardi R, Rondinone R, Di Gangi M, Leonetti C, Canova M, Doria A: Scleroderma-like disorders. Autoimmun Rev. 2008, 331-339. 10.1016/j.autrev.2007.12.004. 7

  89. Azevedo VF, Serafini SZ, Werner B, Müller CS, Franchini CF, Morais RL: Stiff skin syndrome versus scleroderma: a report of two cases. Clin Rheumatol. 2009, 28: 1107-1111. 10.1007/s10067-009-1178-z.

    Article  CAS  PubMed  Google Scholar 

  90. Werner S, Krieg T, Smola H: Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol. 2007, 127: 998-1008. 10.1038/sj.jid.5700786.

    Article  CAS  PubMed  Google Scholar 

  91. Kielty C, Rughunath M, Siracusa LD, Sherratt JJ, Peters R, Shuttleworth CA, Jimenez SA: The tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils. J Cell Biol. 1998, 140: 1159-1166. 10.1083/jcb.140.5.1159.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Gayraud B, Keene DR, Sakai LY, Ramirez F: New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin-1 mutation in the tight skin mouse. J Cell Biol. 2000, 667-680. 10.1083/jcb.150.3.667. 150

  93. Barisic-Dujmovic T, Boban I, Adams DJ, Clark SH: Marfan-like skeletal phenotype in the tight skin (Tsk) mouse. Calcif Tissue Int. 2007, 81: 305-315. 10.1007/s00223-007-9059-4.

    Article  CAS  PubMed  Google Scholar 

  94. Lim D-S, Lutucuta S, Bachireddy P, Youker K, Evans A, Entman M, Roberts R, Marian AJ: Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001, 103: 789-791.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Lavoie P, Robitaille G, Agharazii M, Ledbetter S, Lebel M, Lariviere R: Neutralization of transforming growth factor-β attenuates hypertension and prevents renal injury in uremic rats. Hypertens. 2005, 23: 1895-1903. 10.1097/01.hjh.0000182521.44440.c5.

    Article  CAS  Google Scholar 

  96. Brooke BS, Habashi JP, Judge D, Patel N, Loeys B, Dietz H: Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008, 358: 2787-2795. 10.1056/NEJMoa0706585.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Miller JA, Thai K, Scholey JW: Angiotensin II receptor type I gene polymorphism predicts response to losartan and angiotensin II. Kidney Int. 1999, 56: 2173-2180. 10.1046/j.1523-1755.1999.00770.x.

    Article  CAS  PubMed  Google Scholar 

  98. Arsenault J, Lehoux J, Lanthier L, Cabana J, Guillemette G, Lavigne P, Leduc R, Escher E: A single-nucleotide polymorphism of alanine to threonine at position 163 of the human angiotensin II type 1 receptor impairs Losartan affinity. Pharmacogenet Genomics. 2010, 20: 377-388. 10.1097/FPC.0b013e32833a6d4a.

    Article  CAS  PubMed  Google Scholar 

  99. Chung L, Fiorentino DF, Benbarak JM, Adler AS, Mariano MM, Paniagua RT, Milano A, Connolly MK, Ratiner BD, Wiskocil RL, Whitfield ML, Chang HY, Robinson WH: Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum. 2009, 60: 584-591. 10.1002/art.24221.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Wang S, Wilkes MC, Leof EB, Hirschberg R: Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis. Am J Phys Ren Phys. 2010, F142-F149. 10.1152/ajprenal.00320.2009. 298

  101. Distler JH, Distler O: Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis. 2010, 69 (Suppl 1): i48-i51. 10.1136/ard.2009.120196.

    Article  CAS  PubMed  Google Scholar 

  102. Xiong W, Knispel RA, Dietz HC, Ramirez F, Baxter BT: Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome. J Vasc Surg. 2008, 166-172. 10.1016/j.jvs.2007.09.016. 47

  103. Chung AWY, Yang HHC, Radomsky MW, van Breemen C: Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of metalloproteinases-2 and -9. Circ Res. 2008, 73-85. 10.1161/CIRCRESAHA.108.174367. 102

  104. Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, Meyers J, Leitch CC, Katsanis N, Sharifi N, Xu FL, Myers LA, Spevak PJ, Cameron DE, De Backer J, Hellemans J, Chen Y, Davis EC, Webb CL, Kress W, Coucke P, Rifkin DB, Dietz HC: A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005, 275-281. 10.1038/ng1511. 37

  105. Rossi A, Gabrielli E, Villano M, Messina M, Ferrara F, Weber E: Human microvascular lymphatic and blood endothelial cells produce fibrillin: deposition patterns and quantitative analysis. J Anat. 2010.

    Google Scholar 

Download references


We thank all the members of our laboratories for many stimulating discussions, and Ms. K Johnson for organizing the manuscript. Our work was funded by grants from the National Institutes of Health (AR049698, AR42044 and AR055806) and the Scleroderma Foundation.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Francesco Ramirez.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

JO, SS and FR drafted the manuscript. FR was responsible for its design and coordination. All authors read and approved the final product.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Olivieri, J., Smaldone, S. & Ramirez, F. Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis. Fibrogenesis Tissue Repair 3, 24 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Bone Morphogenetic Protein
  • Bone Morphogenetic Protein Signal
  • Skin Fibrosis
  • Architectural Matrix
  • FBN1 Mutation