Alterations in the extracellular matrix proteoglycan profile in Dupuytren's contracture affect the palmar fascia

Dupuytren's disease is a palmar fibromatosis associated with changes in fibroblast activity that also affect the metabolism of extracellular matrix components. In contrast to disease connected alterations in collagen and non-collagenous glycoproteins (mainly fibronectin), the metabolism of proteoglycans, being glycosaminoglycan modified glycoproteins, is poorly understood. Thus, the aim of the present study was the characterization of matrix proteoglycans (PGs) derived from normal fascia and Dupuytren's fascia. Extracted and purified PGs (particularly small PGs) were analysed for content, molecular mass, immunoreactivity and glycosaminoglycan chain structure. The matrix of normal fascia mainly contains decorin [small dermatan sulfate (DS) PG] with biglycan (another small DSPG) and large chondroitin sulfate(CS)/DSPG representing minor components. Dupuytren's disease is associated with the remodeling of matrix PG composition. The most prominent alteration is an accumulation of biglycan frequently bearing DS chains with higher molecular masses. Moreover, the amount of large CS/DSPG is increased. In contrast, decorin displays changes affecting mainly DS chain structure reflected in (i) an increase in some chain molecular masses, (ii) an enhanced content of iduronate disaccharide clusters, and (iii) oversulfation of disaccharide repeats. The PG alterations observed in Dupuytren's fascia may influence the matrix properties and contribute to disease progression.     

Platelet derived growth factor BB is a ligand for dermatan sulfate chain(s) of small matrix proteoglycans from normal and fibrosis affected fascia

Structural requirements of the short isoform of platelet derived growth factor BB (PDGF-BB) to bind dermatan sulfate (DS)/chondroitin sulfate (CS) are unknown. Meanwhile the interaction may be important for tissue repair and fibrosis which involve both high activity of PDGF-BB and matrix accumulation of DS. We examined by the solid phase assay the growth factor binding to DS chains of small proteoglycans from various fasciae as well as to standard CSs. Before the assay a structural analysis of DSs and CSs was accomplished involving the evaluation of their epimerization and/or sulfation patterns. In addition, in vivo acceptors for PDGF-BB in fibrosis affected fascia were detected. PDGF-BB binding sites on DSs/CSs are located in long chain sections with the same type of hexuronate isomer however without any apparent preference to glucuronate or iduronate residues. Alternatively, the interaction seems to involve two shorter DS chain sections assembling disaccharides with the same type of hexuronate isomer which are separated by disaccharide(s) with another hexuronate one. Moreover, DS/CS affinity to the growth factor most probably depends on an accumulation of di-2,4-O-sulfated disaccharides in binding site while the presence of 6-O-sulfated N-acetyl-galactosamine residues rather attenuates the binding. All examined fascia DSs and standard CSs showed significant PDGF-BB binding capability with the highest affinity found for normal palmar fascia decorin DS. In fibrosis affected palmar fascia DS/CS proteoglycans are able to form with PDGF-BB supramolecular complexes also including other matrix components such as type III collagen and fibronectin which bind the growth factor covalently. Our results suggest that DS chains of fascia matrix small PGs may regulate PDGF-BB availability leading to restriction of fibrosis associated with Dupuytren's disease or to control of normal fascia repair.     

Periostin differentially induces proliferation, contraction and apoptosis of primary Dupuytren's disease and adjacent palmar fascia cells

Dupuytren's disease, (DD), is a fibroproliferative condition of the palmar fascia in the hand, typically resulting in permanent contracture of one or more fingers. This fibromatosis is similar to scarring and other fibroses in displaying excess collagen secretion and contractile myofibroblast differentiation. In this report we expand on previous data demonstrating that POSTN mRNA, which encodes the extra-cellular matrix protein periostin, is up-regulated in Dupuytren's disease cord tissue relative to phenotypically normal palmar fascia. We demonstrate that the protein product of POSTN, periostin, is abundant in Dupuytren's disease cord tissue while little or no periostin immunoreactivity is evident in patient-matched control tissues. The relevance of periostin up-regulation in DD was assessed in primary cultures of cells derived from diseased and phenotypically unaffected palmar fascia from the same patients. These cells were grown in type-1 collagen-enriched culture conditions with or without periostin addition to more closely replicate the in vivo environment. Periostin was found to differentially regulate the apoptosis, proliferation, α smooth muscle actin expression and stressed Fibroblast Populated Collagen Lattice contraction of these cell types. We hypothesize that periostin, secreted by disease cord myofibroblasts into the extra-cellular matrix, promotes the transition of resident fibroblasts in the palmar fascia toward a myofibroblast phenotype, thereby promoting disease progression.     

The surgical treatment of Dupuytren's contracture: a synthesis of techniques

Dupuytren's disease is an affliction of the palmar fascia. Selective fasciectomy is recommended once contracture has occurred. Alternatives for wound closure include tissue rearrangement, the open palm technique, and full-thickness skin grafting. In this prospective study, a new "synthesis" technique was used to treat a cohort of patients with advanced Dupuytren's disease. The results were then compared with those of a second cohort of patients who underwent the open palm technique. Thirty consecutive patients were selected. Ten patients (nine men and one woman; average age, 67 years) underwent the open palm technique, and 20 patients (18 men and two women; average age, 70 years) underwent the synthesis method. Follow-up was 3.5 years for the open palm group and 2.7 years for the synthesis group. All patients in both groups improved with respect to motion, function, appearance, and satisfaction. Objectively, for the open palm technique, metacarpophalangeal joint contracture decreased from 50 degrees to 0 degrees, and proximal interphalangeal joint contracture decreased from 40 degrees to 6 degrees. Using the synthesis method, metacarpophalangeal joint contracture decreased from 57 degrees to 0 degrees, and proximal interphalangeal joint contracture decreased from 58 degrees to 10 degrees. The Disabilities of the Arm, Shoulder, and Hand Test scores decreased from 37 to 30 in both groups. There were no significant differences between groups in these parameters. The two significant intergroup differences were healing time (40 days for the open palm technique versus 28 days for the synthesis method) and recurrence rate (50 percent for open palm versus 0 percent for synthesis). The synthesis technique combines with success the best features of current methods for the surgical treatment of advanced Dupuytren's disease.     

The role of decorin and biglycan dermatan sulfate chain(s) in fibrosis-affected fascia

Organ fibrosis is associated with excessive deposition of dermatan sulfate (DS) in the extracellular matrix (ECM) of the affected tissue. However, the significance of DS in fibrosis process is poorly known. Thus, we have analyzed both in vitro and in vivo the binding potential toward fibroblast growth factor-2, platelet-derived growth factor BB and fibronectin (FN) of DS representing glycosaminoglycan (GAG) chains of two proteoglycans decorin and biglycan derived from fascia undergoing fibrosis due to Dupuytren's disease. Moreover, to investigate the relation between DS structure and its binding properties to above ligands, we have also studied the interactions of the GAG chains from normal porcine skin decorin and biglycan. The examined interactions, especially those engaging extractable pool of both human and porcine decorin DS, are characterized by very high affinity and low capacity. Moreover, the presence of iduronate residues is not essential for the DS binding to all studied ligands and the interactions more strongly depend on the GAG sulfation pattern. All investigated interactions have biological relevance as judged from the coexistence of decorin (and biglycan) DS, both growth factors and FN in supra-molecular complexes localized in ECM of both fibrous and normal human fascia. Moreover, these complexes also include collagen type III. It seems that fascia fibrosis process when compared with physiological circumstances is associated with the preservation of at least some functions of decorin and biglycan DSs such as the regulation of growth factor bioavailability and most probably influence FN fibrillogenesis as well as coupling of various fibrilar matrix element assembly.     

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in sera and tissue of patients with Dupuytren's disease

Dupuytren's contracture is a fibroproliferative disorder characterized by progressive deposition of mature collagen fibers. In other fibrotic diseases affecting organs such as the liver, lung, heart, and skin, matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play an important role. In this study, serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined in 22 patients (five women and 17 men; average age, 67 +/- 11 years) with Dupuytren's disease using an enzyme-linked immunosorbent assay. Tissue samples were obtained for standard histological and immunohistochemical analyses. Sera and samples of palmar fascia from 20 patients (13 women and seven men; average age, 60 +/- 15 years) who had undergone hand surgery for carpal tunnel syndrome were used as the control group. Statistical analysis was performed using the Mann-Whitney test. Patients with Dupuytren's contracture presented with a TIMP-1 concentration of 437 +/- 160 ng/ml, a significantly higher TIMP-1 concentration than that seen in the control patients, who had a concentration of 321 +/- 70 ng/ml (p < 0.05). Patients with a proliferative active disease (n = 14) had a significantly higher TIMP-1 concentration (525 +/- 136 ng/ml) than patients (n = 8) with a contracture in the late involutional and residual phase (286 +/- 41 ng/ml; p < 0.05). There were no significant differences in the TIMP-2, MMP-1, MMP-2, and MMP-9 serum concentrations between patients with palmar fibromatosis and the control group. Patients with Dupuytren's disease had a significantly lower MMP-to-TIMP ratio (1.1 +/- 0.3; p < 0.05) than the control group (1.5 +/- 0.35). Patients with an active palmar fibromatosis presented a significantly (p < 0.05) reduced ratio (1 +/- 0.2) compared with those in later phases (1.4 +/- 0.3). TIMP-1 and TIMP-2 could be detected in tissue of patients with Dupuytren's contracture, with an accumulation in proliferative areas. MMPs could be detected locally in Dupuytren's tissue in a few patients, with less positive staining than for TIMPs. In the control group, there was just little or no staining for TIMPs and MMPs. The data indicate that the physiological balance between MMPs and their natural inhibitors is disturbed in patients with a proliferative active Dupuytren's disease. The decrease in the systemic MMP-to-TIMP ratio can cause increased synthesis and deposition of collagen, leading to palmar fibromatosis.     

Dermatan sulfates of normal and scarred fascia

We evaluated the composition of dermatan sulfates (DS) derived from 23 samples of normal and 23 samples of scarred fascia lata. We analyzed the molecular weight of intact DS chains and the length of chain regions comprising: (1) clusters of L-iduronate-containing disaccharides ("iduronic sections"); (2) clusters of D-glucuronate-containing disaccharides ("glucuronic sections"); and (3) copolymeric sections with both types of disaccharides. A portion of scarred fascia DS chains demonstrated higher molecular weight compared with those from normal tissue. Most disaccharides of DS chains derived from both fascia types form copolymeric segments - heterogeneous in size - with alternatively distributed single disaccharides with glucuronic residues and mainly single ones with iduronate. Only a small number of disaccharides form "glucuronic sections" of heterogeneous size or short "iduronic sections". However, the scarred fascia DS chains demonstrate an increased content of shorter "glucuronic sections" and shorter, often oversulfated, copolymeric segments. It seems that in normal fascia, the DS chain type with a single, long copolymeric region and a single, shorter "glucuronic section" is predominant, while in scarred tissue an increase in multidomain DS chain content may occur.     

Characterization of implants from Dupuytren's contracture tissue into the nude (athymic) mouse

Dupuytren's contracture tissues were obtained from six patients as excess surgical material. Pieces of these tissues (a total of 38 implants) were placed into subcutaneous pockets in the suprascapular area of nude (athymic) mice. The objective was to determine whether the implant tissues would be maintained in the mouse with the characteristics of Dupuytren's tissue. The implants were removed for study at 14-179 days after implantation. Microvascular anastomosis between implant and host skin was established within the first 14 days. Histologic character and electron microscopic structure of the implants did not change during the course of the study. The implants became reduced in size with time. However, neither the spatial pattern of collagen nor the appearance of fibroblast cells changed. The original high levels of chondroitin-4-sulfate were significantly decreased in the 66- to 179-day postimplantation group, but were not significantly different from the values for normal fascial bands. The hyaluronic acid of the implants increased significantly with time of implantation, but never reached the level found in the normal fascial bands. The use of implants into nude mice may be useful for further experimental studies of Dupuytren's contracture.     

Dupuytren's disease: physiologic changes in nodule and cord fibroblasts through aging in vitro

The pathogenesis of the fibrotic disease Dupuytren's contracture remains unclear. The disease process includes two structurally distinct fibrotic elements, the nodule and the cord. It has been proposed that as the disease progresses, nodules develop into cords. To corroborate that hypothesis, the authors took advantage of cultured fibroblast differences found between gap junction intercellular communication and fibroblast-populated collagen lattice contraction. Paired fibroblast cell lines of nodules and cords derived from four patients with Dupuytren's disease were maintained in culture for at least eight passages. The presence of gap junction intercellular communication in nodule- and cord-derived fibroblasts was documented and reported as a coupling index. The contraction of free-floating nodule- or cord-derived collagen lattices was also documented and reported. Early passage (passage 4) cord-derived fibroblasts showed a significant increase in coupling index compared with passage 4 nodule-derived fibroblasts (4.0 +/- 0.4 versus 2.5 +/- 0.3, respectively), where p < or = 0.01. However, late passage (passage 8) nodule- and cord-derived fibroblasts were equivalent in their coupling index (4.1 +/- 0.4 versus 4.4 +/- 0.4, respectively). Early passage nodule-derived fibroblast-populated collagen lattices contracted by 64 percent, whereas late passage nodule-derived lattices showed less contraction, at only 40 percent. Early and late passage cord-derived lattices contracted 46 and 37 percent, respectively. All nodule- and cord-derived cell lines were statistically equivalent at lattice contraction by passage 8. These in vitro studies support the hypothesis that fibroblasts derived from Dupuytren's contracture nodules change their phenotype after undergoing repeated cell passage, acquiring a cord-like fibroblast phenotype. Dupuytren's nodules represent the early, active form of fibrosis in which cells are more proliferative, better at fibroblast-populated collagen lattice contraction, and display less gap junction intercellular communication. The speculation is that alterations in gap junction intercellular communication may be involved in the progression of Dupuytren's nodules to cords as the disease progresses.     

Structural alteration of glycosaminoglycan side chains and spatial disorganization of collagen networks in the skin of patients with mcEDS-CHST14

Musculocontractural Ehlers-Danlos syndrome (mcEDS) due to CHST14/D4ST1 deficiency (mcEDS-CHST14) is a recently delineated type of EDS caused by biallelic loss-of-function mutations in CHST14, which results in the depletion of dermatan sulfate (DS). Clinical characteristics of mcEDS-CHST14 consist of multiple malformations and progressive fragility-related manifestations, including skin hyperextensibility and fragility. Skin fragility is suspected to result from the impaired assembly of collagen fibrils caused by alteration of the glycosaminoglycan (GAG) chain of decorin-proteoglycan (PG) from DS to chondroitin sulfate (CS). This systematic investigation of the skin pathology of patients with mcEDS-CHST14 comprised both immunostaining of decorin and transmission electron microscopy-based cupromeronic blue staining to visualize GAG chains. Collagen fibrils were dispersed in the affected papillary to reticular dermis; in contrast, they were regularly and tightly assembled in controls. Moreover, the fibrils exhibited a perpendicular arrangement to the affected epidermis, whereas fibrils were parallel to control epidermis. Affected GAG chains were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils; in contrast, those of controls were curved, maintaining close contact with attached collagen fibrils. This is the first observation of compositional alteration, from DS to CS, of GAG side chains, which caused structural alteration of GAG side chains and resulted in spatial disorganization of collagen networks; this presumably disrupted the ring-mesh structure of GAG side chains surrounding collagen fibrils. McEDS-CHST14 provides a critical example of the importance of DS in GAG side chains of decorin-PG during assembly of collagen fibrils in maintenance of connective tissues.     

The human rhabdomyosarcoma cell line A204 lays down a highly insoluble matrix composed mainly of alpha 1 type-XI and alpha 2 type-V collagen chains.

The biosynthesis of collagen by the A204 cell line was examined using polyclonal antibodies raised against collagen type V and type XI. The study of the pepsin-digested collagen showed that it is composed mainly of alpha 1(XI) and alpha 2(V) collagen chains in an apparent 2:1 ratio, suggesting the formation of heterotypic molecules [alpha 1(XI)]2 alpha 2(V). The existence of this chain stoichiometry was further demonstrated by immunoprecipitation of the molecule with an antibody recognizing alpha 2(V) but not alpha 1(XI) collagen chains. Electron microscopy analyses of 24-h cultures showed that this matrix is composed of thin fibrils, that can be decorated with immunogold-labelled anti-(type-V collagen) IgG, but not with anti-(type-XI collagen) IgG. The collagen matrix laid down by A204 cells is highly insoluble. In the presence of beta-aminopropionitrile, an inhibitor of lysyl oxidase, only a small proportion of intact collagen could be extracted without proteolytic treatment. Immunoblotting of intact medium collagen from cultures performed in the presence of beta-aminopropionitrile showed four distinct bands with each antibody. The migration of the bands, stained with anti-(type-V collagen) IgG, had apparent molecular masses of 127, 149, 161 and 198 kDa (compared to globular standards) while the bands stained with anti-(type-XI collagen) IgG had apparent masses of 145, 182, 207 and 225 kDa. These data indicate that type-V and type-XI collagen chains can assemble in heterotypic isoforms. In this system, the synthesized isoforms are able to aggregate into a highly cohesive matrix and they undergo a proteolytic processing closely similar to that of other fibrillar collagens.     

Rheumatoid arthritis and Dupuytren's contracture

Of four patients with rheumatoid arthritis and Dupuytren's contracture, two were not aware of the presence of Dupuytren's contracture. When both diseases coexist, the presence of rheumatoid hand deformities, especially flexion and ulnar deviation of the metacarpophalangeal joints, may mask the flexion deformity caused by Dupuytren's contracture. Careful clinical examination should rule out the presence of a pathologic fascial cord. When reconstructive surgery is indicated for the rheumatoid hand in the presence of advanced Dupuytren's contracture, staged surgery would be appropriate and reconstruction of Dupuytren's contracture should precede other surgery.     

Distinct maturations of N-propeptide domains in fibrillar procollagen molecules involved in the formation of heterotypic fibrils in adult sea urchin collagenous tissues

We have characterized the primary structure of a new sea urchin fibrillar collagen, the 5alpha chain, including nine repeats of the sea urchin fibrillar module in its N-propeptide. By Western blot and immunofluorescence analyses, we have shown that 5alpha is co-localized in adult collagenous ligaments with the 2alpha fibrillar collagen chain and fibrosurfin, two other extracellular matrix proteins possessing sea urchin fibrillar modules. At the ultrastructural level, the 5alpha N-propeptide is detected at the surface of fibrils, suggesting the retention of this domain in mature collagen molecules. Biochemical characterization of pepsinized collagen molecules extracted from the test tissue (the endoskeleton) together with a matrix-assisted laser desorption ionization time-of-flight analysis allowed us to determine that 5alpha is a quantitatively minor fibrillar collagen chain in comparison with the 1alpha and 2alpha chains. Moreover, 5alpha forms heterotrimeric molecules with two 1alpha chains. Hence, as in vertebrates, sea urchin collagen fibrils are made up of quantitatively major and minor fibrillar molecules undergoing distinct maturation of their N-propeptide regions and participating in the formation of heterotypic fibrils.     

Analysis of novel over‐ and under‐sulfated glycosaminoglycan sequences by enzyme cleavage and multiple stage MS

We report on a novel strategy for identification of specific sulfation motifs in chondroitin/dermatan sulfate (CS/DS) chain derived from decorin (Dcn), based on enzyme cleavage and multistage MS (MSⁿ). Released CS/DS chains were digested with chondroitin B and in parallel with AC I lyases to obtain oligosaccharides of known hexuronic acid (HexA) epimerization. The depolymerized chains were separated by gel filtration, and collected di‐ and hexasaccharides were analyzed by ESI MSⁿ. MS² on bisulfated 4,5‐Δ‐HexAGalNAc revealed an additional sulfate ester group at 4,5‐Δ‐HexA. MS² data provided evidence upon GlcA sulfation in Dcn due to the fact that 4,5‐Δ‐HexA derived from GlcA after chondroitin AC I lyase treatment. Hexasaccharide screening in the MS¹ mode indicated direct correlation between the sulfate distribution and HexA epimerization. MSⁿ performed on ions that, according to mass calculation, correspond to pentasulfated [4,5‐Δ‐HexAGalNAc(GlcAGalNAc)₂], trisulfated [4,5‐Δ‐HexAGalNAc(GlcAGalNAc)₂] with IdoA‐derived 4,5‐Δ‐HexA at the nonreducing end, tetrasulfated [4,5‐Δ‐HexAGalNAc(IdoAGalNAc)₂] and monosulfated [4,5‐Δ‐HexAGalNAc(IdoAGalNAc)₂] with GlcA‐derived 4,5‐Δ‐HexA at the nonreducing end rendered fragmentation patterns confirming the presence of over‐, regular, and under‐sulfated regions as well as structural motifs having both types of HexA sulfated within Dcn CS/DS.     

Collagen matrix remodeling in 3-dimensional cellular space resolved using second harmonic generation and multiphoton excitation fluorescence

The structural remodeling of collagen is important in biological processes such as fibrosis, developmental morphogenesis and wound repair. Highly ordered collagen macromolecules produce second harmonic generation signals without the need for any exogenous label. Conversely, the cellular components stained with exogenous labels generate multiphoton excitation fluorescence signals. Both these signals can be captured simultaneously to provide spatially resolved structural reorganization of a collagen matrix and cells. This study dealt with an in vitro collagen gel contraction model of wound repair, in which fibroblasts are seeded into a 3-dimensional type I collagen matrix. When cells are stimulated to trigger collagen contraction, we found the fibroblasts to be highly elongated as well as interconnected in 2-dimensional space, and the collagen, in the form of a visibly clear fibril structure, accumulated around the cells. In the absence of contraction, on the other hand, the cells were predominantly round in shape and no sign of collagen accumulation around the cell was evident despite the presence of the fibrillar collagen morphology in the matrix. Our data suggest second harmonic and multiphoton excitation fluorescence signals can be used in tandem to provide spatially resolved 3-dimensional structural remodeling of a collagen matrix during wound repair.     

Type I collagen triplet duplication mutation in lethal osteogenesis imperfecta shifts register of alpha chains throughout the helix and disrupts incorporation of mutant helices into fibrils and extracellular matrix

The majority of collagen mutations causing osteogenesis imperfecta (OI) are glycine substitutions that disrupt formation of the triple helix. A rare type of collagen mutation consists of a duplication or deletion of one or two Gly-X-Y triplets. These mutations shift the register of collagen chains with respect to each other in the helix but do not interrupt the triplet sequence, yet they have severe clinical consequences. We investigated the effect of shifting the register of the collagen helix by a single Gly-X-Y triplet on collagen assembly, stability, and incorporation into fibrils and matrix. These studies utilized a triplet duplication in COL1A1 exon 44 that occurred in the cDNA and gDNA of two siblings with lethal OI. The normal allele encodes three identical Gly-Ala-Hyp triplets at aa 868-876, whereas the mutant allele encodes four. The register shift delays helix formation, causing overmodification. Differential scanning calorimetry yielded a decrease in T(m) of 2 degrees C for helices with one mutant chain and a 6 degrees C decrease in helices with two mutant chains. An in vitro binary co-processing assay of N-proteinase cleavage demonstrated that procollagen with the triplet duplication has slower N-propeptide cleavage than in normal controls or procollagen with proalpha1(I) G832S, G898S, or G997S substitutions, showing that the register shift persists through the entire helix. The register shift disrupts incorporation of mutant collagen into fibrils and matrix. Proband fibrils formed inefficiently in vitro and contained only normal helices and helices with a single mutant chain. Helices with two mutant chains and a significant portion of helices with one mutant chain did not form fibrils. In matrix deposited by proband fibroblasts, mutant chains were abundant in the immaturely cross-linked fraction but constituted a minor fraction of maturely cross-linked chains. The profound effects of shifting the collagen triplet register on chain interactions in the helix and on fibril formation correlate with the severe clinical consequences.     

Role of the α1β1 integrin complex in collagen gel contraction in vitro by fibroblasts

Matrix remodeling, critical to embryonic morphogenesis and wound healing, is dependent on the expression of matrix components, their receptors, and matrix proteases. The collagen gel assay has provided an effective model for the examination of the functional role(s) of each of these groups of molecules in matrix remodeling. Previous investigations have indicated that collagen gel contraction involves the β1 integrin family of matrix receptors and is stimulated by several growth factors, including TGF-β, PDGF, and angiotensin II. In particular, collagen gel remodeling by human cells involves the α2β1 and, to a lesser extent the α1β1 integrin complexes. The present studies were undertaken to determine the role of the α1 integrin chain, a collagen/laminin receptor, in collagen gel contration by rodent and avian fibroblasts. A high degree of correlation was found between the expression of the α1β1 integrin complex and the relative ability of cells to contract collagen gels. Further studies using antibodies and antisense oligonucleotides against the α1 integrin indicated a significant role for this integrin chain in contraction of collagen gels by rat cardiac fibroblasts. In addition, antibodies to the α1 integrin chain inhibited migration of these fibroblasts on a collagen substratum, suggesting that at least one role of this integrin is in migration of cells in collagen gels. These results indicate that the α1β integrin complex plays a significant role in cellular interactions with interstital collagen that are involved in matrix remodeling such as is seen during morphogenesis and wound healing. © 1995 Wiley-Liss, Inc.