Small Leucine-rich Proteoglycan Research Articles

Sequence features, structure, ligand interaction, and diseases in small leucine rich repeat proteoglycans.

Small leucine rich repeat proteoglycans (SLRPs) are a group of active components of the extracellular matrix in all tissues. SLRPs bind to collagens and regulate collagen fibril growth and fibril organization. SLRPs also interact with various cytokines and extracellular compounds, which lead to various biological functions such cell adhesion and signaling, proliferation, and differentiation. Mutations in SLRP genes are associated with human diseases. Now crystal structures of five SLRPs are available. We describe some features of amino acid sequence and structures of SLRPs. We also review ligand interactions and then discuss the interaction surfaces. Furthermore, we map mutations associated with human diseases and discuss possible effects on structures by the mutations.

Osteomodulin impacts positively the bone remodeling process in osteoarthritis

Purpose: Osteomodulin (OMD) is a Small Leucine Rich Proteoglycan (SLRP) highly specific of the bone extracellular matrix. Its production and expression are impaired in subchondral bone sclerosis associated with osteoarthritis (OA). This study aimed to investigate the effects OMD on osteoblasts and osteoclasts in culture.

Novel roles of Tsukushi in signaling pathways and multiple disease processes.

Tsukushi (TSK), a newly identified hepatokine, is a member of the small leucine-rich proteoglycans (SLRPs) family. TSK was originally isolated and identified in the lens of the chicken. Preliminary research on TSK has focused on its role in various physiological processes such as growth and development, wound healing, and cartilage formation. In recent years, the role of TSK in regulating cell signaling pathways, cell proliferation, and differentiation has been studied. In addition, the research has gradually expanded to the fields of glycolipid metabolism and energy balance. This article briefly reviews the role of TSK in the physiological and pathological process.

The Extracellular Small Leucine-Rich Proteoglycan Biglycan Is a Key Player in Gastric Cancer Aggressiveness.

Simple SummaryApproximately 80% of gastric cancer patients are diagnosed at advanced stages with an average five-year survival rate of less than 30%. Alterations of the extracellular matrix proteins have been largely demonstrated in all steps of the disease. Thus, studies for the identification of novel prognostic biomarkers and efficient therapeutic strategies are urgently needed. In this study, we report the oncogenic role of biglycan, an extracellular proteoglycan, in gastric carcinogenesis. Biglycan was able to modulate gastric cancer aggressive features as cell survival, migration, and angiogenesis. Additionally, high levels of biglycan expression correlates with tumorigenic gene signatures and they are associated with poor patient prognosis in advanced stages of the disease. These results point biglycan as a key player in gastric cancer aggressiveness and further studies should be done to investigate the therapeutic potential of biglycan to tackle gastric cancer progression.Biglycan (BGN gene), an extracellular proteoglycan, has been described to be associated with cancer aggressiveness. The purpose of this study was to clarify the clinical value of biglycan as a biomarker in multiple independent GC cohorts and determine the in vitro and in vivo role of biglycan in GC malignant features. We found that BGN is commonly over-expressed in all analyzed cohorts, being associated with disease relapse and poor prognosis in patients with advanced stages of disease. In vitro and in vivo experiments demonstrated that biglycan knock-out GC cells display major phenotypic changes with a lower cell survival, migration, and angiogenic potential when compared with biglycan expressing cells. Biglycan KO GC cells present increased levels of PARP1 and caspase-3 cleavage and a decreased expression of mesenchymal markers. Importantly, biglycan deficient GC cells that were supplemented with exogenous biglycan were able to restore biological features, such as survival, clonogenic and migratory capacities. Our in vitro and in vivo findings were validated in human GC samples, where BGN expression was associated with several oncogenic gene signatures that were associated with apoptosis, cell migration, invasion, and angiogenesis. This study provided new insights on biglycan role in GC that should be taken in consideration as a key cellular regulator with major impact in tumor progression and patients’ clinical outcome.

Different expression of lumican glycoforms in non-metastatic and metastatic laryngeal squamous cell carcinoma

Objective: Association of altered growth factor receptors-mediated intracellular pathways and biological processes associated with extracellular matrix composition and structure in laryngeal squamous cell carcinoma (LSCC) were described previously. In particular, the expression and glycosylation of important extracellular matrix molecules (ECM) such as small leucine rich proteoglycan lumican, may be generally associated with disrupted extracellular matrix integrity and inflammation processes which have a role in tumour invasiveness. In this study, the relative expression of different lumican glycoforms were evaluated in primary tumour and tumour-unaffected tissue samples of ten patients with metastatic and ten non-metastatic LSCC by Western blot and 2D immunoblot analysis. Materials and methods: Tissue samples from the primary tumours and paired adjacent non-tumour tissues were surgically resected from ten untreated LSCC patients with non-metastatic disease and ten LSCC patients with lymph nodes metastases. The relative expression of different lumican glycoforms in primary tumours and paired adjacent non-tumour tissues were evaluated by Western blot and 2D immunoblot analysis. Results: Results of Western blot analysis have revealed elevated expression of the moderately glycosylated lumican form in metastatic (p<0,05) and non-metastatic primary tumour tissues in comparison with tumour unaffected tissues. In addition, moderately glycosylated form of lumican with negatively charged oligosaccharide residues in the N-glycan molecule part was exclusively determined in metastatic primary tumour tissues by 2D immunoblot analysis. Conclusion: We demonstrated elevated expression of the moderately glycosylated lumican form with negatively charged oligosaccharide residues in the N-glycan portion exclusively in primary laryngeal squamous cell carcinoma from patients with metastatic disease.

A novel ocular function for decorin in the aqueous humor outflow

Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide. Several randomized multicenter studies have identified intraocular pressure as the major risk factor for its development, caused by an increased outflow resistance to the aqueous humor within the trabecular meshwork. However, the molecular mechanism for increased outflow resistance in POAG has not been fully established. One of the proposed players is the pro-fibrotic transforming growth factor (TGF)-β2, which is found in higher amounts in the aqueous humor of patients with POAG. In this study we elucidated the role of decorin, a small leucine-rich proteoglycan and known antagonist of TGF-β, in the region of aqueous humor outflow tissue. Utilizing decorin deficient mice, we discovered that decorin modulated TGF-β signaling in the canonical outflow pathways and the lack of decorin in vivo caused an increase in intraocular pressure. Additionally, the Dcn−/− mice showed significant loss of optic nerve axons and morphological changes in the glial lamina, typical features of glaucoma. Moreover, using human trabecular meshwork cells we discovered that soluble decorin attenuated TGF-β2 mediated synthesis and expression of typical downstream target genes including CCN2/CTGF, FN and COL IV. Finally, we found a negative reciprocal regulation of decorin and TGF-β, with a dramatic downregulation of decorin in the canonical outflow pathways of patients with primary open-angle glaucoma. Collectively, our results indicate that decorin plays an important role in the pathogenesis of primary open-angle glaucoma and offers novel perspectives in the treatment of this serious disease.

Spatial survey of non-collagenous proteins in mineralizing and non-mineralizing vertebrate tissues ex vivo

Bone biomineralization is a complex process in which type I collagen and associated non-collagenous proteins (NCPs), including glycoproteins and proteoglycans, interact closely with inorganic calcium and phosphate ions to control the precipitation of nanosized, non-stoichiometric hydroxyapatite (HAP, idealized stoichiometry Ca10(PO4)6(OH)2) within the organic matrix of a tissue. The ability of certain vertebrate tissues to mineralize is critically related to several aspects of their function. The goal of this study was to identify specific NCPs in mineralizing and non-mineralizing tissues of two animal models, rat and turkey, and to determine whether some NCPs are unique to each type of tissue. The tissues investigated were rat femur (mineralizing) and tail tendon (non-mineralizing) and turkey leg tendon (having both mineralizing and non-mineralizing regions in the same individual specimen). An experimental approach ex vivo was designed for this investigation by combining sequential protein extraction with comprehensive protein mapping using proteomics and Western blotting. The extraction method enabled separation of various NCPs based on their association with either the extracellular organic collagenous matrix phases or the inorganic mineral phases of the tissues. The proteomics work generated a complete picture of NCPs in different tissues and animal species. Subsequently, Western blotting provided validation for some of the proteomics findings. The survey then yielded generalized results relevant to various protein families, rather than only individual NCPs. This study focused primarily on the NCPs belonging to the small leucine-rich proteoglycan (SLRP) family and the small integrin-binding ligand N-linked glycoproteins (SIBLINGs). SLRPs were found to be associated only with the collagenous matrix, a result suggesting that they are mainly involved in structural matrix organization and not in mineralization. SIBLINGs as well as matrix Gla (γ-carboxyglutamate) protein were strictly localized within the inorganic mineral phase of mineralizing tissues, a finding suggesting that their roles are limited to mineralization. The results from this study indicated that osteocalcin was closely involved in mineralization but did not preclude possible additional roles as a hormone. This report provides for the first time a spatial survey and comparison of NCPs from mineralizing and non-mineralizing tissues ex vivo and defines the proteome of turkey leg tendons as a model for vertebrate mineralization.

Osteomodulin positively regulates osteogenesis through interaction with BMP2

Osteomodulin (OMD), a member of the small leucine-rich proteoglycan family, distributes in mineralized tissues and is positively regulated by bone morphogenetic protein 2 (BMP2). However, the exact function of OMD during mineralization and its association with BMP2 remain poorly understood. Herein, the expression pattern of OMD during osteogenesis was investigated in human dental pulp stem cells. Silencing OMD gene significantly suppressed the alkaline phosphatase activity, mineralized nodule formation and osteogenesis-associated gene transcription. Besides, OMD could enhance BMP2-induced expression of SP7 and RUNX2 with concentration dependence in vitro. Rat mandibular bone defect model revealed that scaffolds injected with the combination of OMD and suboptimal BMP2 exhibited more mature and abundant mineralized bone than that treated with OMD or suboptimal BMP2 alone. Mechanistically, OMD could bind to BMP2 via its terminal leucine-rich repeats and formed complexes with BMP2 and its membrane receptors, thus promoting BMP/SMAD signal transduction. In addition, OMD was a putative target gene of SMAD4, which plays a pivotal role in this pathway. Collectively, these data elucidate that OMD may act as a positive coordinator in osteogenesis through BMP2/SMADs signaling.

Lumican inhibits immune escape and carcinogenic pathways in colorectal adenocarcinoma.

Lumican (LUM), a small leucine-rich proteoglycan, is a component of the extracellular matrix. Abnormal LUM expression is potentially associated with cancer progression. In the present study, we confirmed high LUM mRNA expression in colorectal adenocarcinoma (COAD) through the UALCAN database. The Kaplan-Meier method, univariate, and multivariate COX analysis showed that high LUM expression is an independent determinant of poor prognosis in COAD. A COX regression model was constructed based on clinical information and LUM expression. The receiver operating characteristic (ROC) curve indicated that this model was highly accurate in monitoring COAD prognosis. The co-expression network of LUM was determined by LinkedOmics, which showed that LUM expression was closely related to immune escape and the miR200 family. Furthermore, we studied the co-expression network of LUM and found that LUM could promote tumor metastasis and invasion. The Tumor Immune Estimation Resource website showed that LUM was closely related to immune infiltration and correlated with regulatory T cells, tumour-associated macrophages, and dendritic cells. We found that LUM cultivated cancer progression by targeting the miR200 family to promote epithelial-to-mesenchymal transition. These findings suggest that LUM is a potential target for inhibiting immune escape and carcinogenic pathways.

Decorin-mediated suppression of tumorigenesis, invasion, and metastasis in inflammatory breast cancer

Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited tumor growth and metastasis in IBC xenograft mouse models. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.

Proteoglycans and Diseases of Soft Tissues.

Proteoglycans consist of protein cores to which at least one glycosaminoglycan chain is attached. They play important roles in the physiology and biomechanical function of tendons, ligaments, cardiovascular system, and other systems through their involvement in regulation of assembly and maintenance of extracellular matrix, and through their participation in cell proliferation together with growth factors. They can be divided into two main groups, small and large proteoglycans. The small proteoglycans are also known as small leucine-rich proteoglycans (SLRPs) which are encoded by 18 genes and are further subclassified into Classes I-V. Several members of Class I and II, such as decorin and biglycan from Class I, and Class II fibromodulin and lumican, are known to regulate collagen fibrillogenesis. Decorin limits the diameter of collagen fibrils during fibrillogenesis. The function of biglycan in fibrillogenesis is similar to that of decorin. Though biomechanical function of tendon is compromised in decorin-deficient mice, decorin can substitute for lack of biglycan in biglycan-deficient mice. New data also indicate an important role for biglycan in disorders of the cardiovascular system, including aortic valve stenosis and aortic dissection. Two members of the Class II of SLRPs, fibromodulin and lumican bind to the same site within the collagen molecule and can substitute for each other in fibromodulin- or lumican-deficient mice.Aggrecan and versican are the major representatives of the large proteoglycans. Though they are mainly found in the cartilage where they provide resilience and toughness, they are present also in tensile portions of tendons and, in slightly different biochemical form in fibrocartilage. Degradation by aggrecanase is responsible for the appearance of different forms of aggrecan and versican in different parts of the tendon where these cleaved forms play different roles. In addition, they are important components of the ventricularis of cardiac valves. Mutations in the gene for versican or in the gene for elastin (which binds to versican ) lead to severe disruptions of normal developmental of the heart at least in mice.

Proteomic identification and validation of novel interactions of the putative tumor suppressor PRELP with membrane proteins including IGFI-R and p75NTR

Proline and arginine-rich end leucine-rich repeat protein (PRELP) is a member of the small leucine-rich repeat proteoglycans (SLRPs) family. Levels of PRELP mRNA are downregulated in many types of cancer, and PRELP has been reported to have suppressive effects on tumor cell growth, although the molecular mechanism has yet to be fully elucidated. Given that other SLRPs regulate signaling pathways through interactions with various membrane proteins, we reasoned that PRELP likely interacts with membrane proteins to maintain cellular homeostasis. To identify membrane proteins that interact with PRELP, we carried out coimmunoprecipitation coupled with mass spectrometry (CoIP-MS). We prepared membrane fractions from Expi293 cells transfected to overexpress FLAG-tagged PRELP or control cells and analyzed samples precipitated with anti-FLAG antibody by mass spectrometry. Comparison of membrane proteins in each sample identified several that seem to interact with PRELP; among them, we noted two growth factor receptors, insulin-like growth factor I receptor (IGFI-R) and low-affinity nerve growth factor receptor (p75NTR), interactions with which might help to explain PRELP’s links to cancer. We demonstrated that PRELP directly binds to extracellular domains of these two growth factor receptors with low micromolar affinities by surface plasmon resonance analysis using recombinant proteins. Furthermore, cell-based analysis using recombinant PRELP protein showed that PRELP suppressed cell growth and affected cell morphology of A549 lung carcinoma cells, also at micromolar concentration. These results suggest that PRELP regulates cellular functions through interactions with IGFI-R and p75NTR and provide a broader set of candidate partners for further exploration.

High expression of LUM independently predicts poor prognosis in gastric cancer: a bioinformatics study combining TCGA and GEO datasets

LUM, a less-explored member of small leucine-rich proteoglycan family, has gained growing concern with controversial roles in tumor prognosis in recent years. The function of LUM in gastric cancer remains rarely reported and largely unclear. In this study, we investigated the expression of LUM in gastric cancer as well as its association with clinical parameters. Data from the GEO and Human Protein Atlas (HPA) databases are used for further validation. GC tissue shows significantly high expression of LUM compared with normal tissue (P < 0.001). High expression of LUM is correlated with poor differentiation, advanced tumor stage, deeper local invasion and worse overall survival. Patients with high expression of LUM have significantly worse prognosis than those with low expression. Multivariate analysis shows that high expression of LUM is an independent risk factor for overall survival. Several biomolecular pathways, including extracellular matrix receptor interaction, melanoma, cancer, chemokine signaling, Toll-like receptor signaling and Wnt signaling, are screened out as significantly enriched in GCs with high LUM expression using GSEA. Our study reveals that LUM, as an independent predictor, is highly expressed and associated with clinicopathologic factors in gastric cancer, demonstrating potential applications in prognosis of patient with gastric cancer.

Meester-Loeys Syndrome.

Meester-Loeys syndrome is an X-linked form of syndromic thoracic aortic aneurysm, characterized by the involvement of multiple organ systems. More specifically, the cardiovascular, skeletal, craniofacial, cutaneous and neurological systems are affected. Clear clinical overlap with Marfan syndrome and Loeys-Dietz syndrome is observed. Aortic dissections occur typically at young ages and are most often observed in males. Meester-Loeys syndrome is caused by loss-of-function mutations in BGN, encoding the small leucine-rich proteoglycan biglycan. Although functional consequences of these mutations remain largely elusive, increased TGF-β signaling has been observed. Novel insights will provide opportunities for preventive therapeutic interventions.

Proteomic Analysis and Cell Viability of Nine Amnion, Chorion, Umbilical Cord, and Amniotic Fluid-Derived Products.

Amnion products are used in various musculoskeletal surgeries and as injections for joint pain with conflicting reports of cell viability and protein contents. The objective of this study was to determine the full proteome and examine cell viability in 9 commercial amnion products using an unbiased bottom-up shotgun proteomics approach and confocal microscopy. Products were subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and searched against a UniProt Homo sapiens database. Relative protein abundance was determined for each sample. Based on proteomics results, lumican was measured by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis was performed for interleukin-1 receptor antagonist (IL-1Ra) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2). Cell viability was determined by calcein AM (live) and ethidium homodimer (dead) staining and confocal microscopy. Proteomic analysis revealed 919 proteins in the nine products. Proteins were primarily collagens, keratin, and albumin. Lumican, a small leucine-rich proteoglycan (SLRP) was found in all samples. Western blot analysis for IL-1Ra and TIMP-2 indicated presence of both proteins, with nonspecific antibody binding also present in all samples. No live cells were identified in any product. Several novel proteins were identified through proteomics that might impart the beneficial effects of amnion products, including SLRPs, collagens, and regulators of fibroblast activity. IL-1Ra and TIMP-2 were identified, but concentrations measured by ELISA may be falsely increased due to nonspecific antibody binding. The concept that the amnion tissues provide live cells to aid in tissue regeneration cannot be supported by the findings of this study.

Decorin regulates cartilage pericellular matrix micromechanobiology

In cartilage tissue engineering, one key challenge is for regenerative tissue to recapitulate the biomechanical functions of native cartilage while maintaining normal mechanosensitive activities of chondrocytes. Thus, it is imperative to discern the micromechanobiological functions of the pericellular matrix, the ~ 2–4 µm-thick domain that is in immediate contact with chondrocytes. In this study, we discovered that decorin, a small leucine-rich proteoglycan, is a key determinant of cartilage pericellular matrix micromechanics and chondrocyte mechanotransduction in vivo. The pericellular matrix of decorin-null murine cartilage developed reduced content of aggrecan, the major chondroitin sulfate proteoglycan of cartilage and a mild increase in collagen II fibril diameter vis-à-vis wild-type controls. As a result, decorin-null pericellular matrix showed a significant reduction in micromodulus, which became progressively more pronounced with maturation. In alignment with the defects of pericellular matrix, decorin-null chondrocytes exhibited decreased intracellular calcium activities, [Ca2+]i, in both physiologic and osmotically evoked fluidic environments in situ, illustrating impaired chondrocyte mechanotransduction. Next, we compared [Ca2+]i activities of wild-type and decorin-null chondrocytes following enzymatic removal of chondroitin sulfate glycosaminoglycans. The results showed that decorin mediates chondrocyte mechanotransduction primarily through regulating the integrity of aggrecan network, and thus, aggrecan-endowed negative charge microenvironment in the pericellular matrix. Collectively, our results provide robust genetic and biomechanical evidence that decorin is an essential constituent of the native cartilage matrix, and suggest that modulating decorin activities could improve cartilage regeneration.

An in situ hybridization study of decorin and biglycan mRNA in mouse osteoblasts in vivo.

In situ hybridization of decorin and biglycan mRNA, principal members of small leucine-rich proteoglycan, was performed using [35S]-labeled RNA probes, in the context of the hypothesis that they show different expression patterns associated with osteoblast differentiation in mice. We adopted two ossifying sites that can clearly follow the developmental process of bone formation: ossifying tympanic ring and developing bone collar of mandibular condylar cartilage. Decorin mRNA was expressed in osteoblasts of developing tympanic ring at E14.0, as well as of developing bone collar at E15.0, but biglycan mRNA was not, indicating decorin mRNA was expressed earlier in newly differentiating osteoblasts than biglycan. With maturation of osteoblasts, biglycan mRNA became expressed and maintained its expression both in the outer region (periosteum) and in the interior region (endosteum) of bone. By contrast, decorin mRNA expression was maintained in the outer region but diminished in the interior region. These results indicate that decorin and biglycan show differential expression patterns in differentiating osteoblasts and play specific roles in bone formation.

Two Secreted Proteoglycans, Activators of Urothelial Cell-Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression.

Simple SummaryEpithelial–mesenchymal transition (EMT) is associated with cancer progression. Here, we found that two secreted proteins of osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) were selectively expressed in bladder umbrella epithelial cells, and they were suppressed in bladder cancer. We revealed that OMD−/− or PRELP−/− knockout mice caused a breakdown of the umbrella cell layer through weakening cell–cell integrity and the activation of partial EMT, which resulted in the formation of early bladder cancer-like structures, while OMD or PRELP application to bladder cancer cells inhibited cancer progression through reversing EMT, which was mediated by the inhibition of TGF-β and EGF. Our result indicates that OMD and PRELP function as tumor-suppressing proteins through inhibiting EMT. OMD and PRELP may be potential therapeutic targets in bladder cancer.Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial–mesenchymal transition (EMT), activated cell–cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.

Distinct effects of different matrix proteoglycans on collagen fibrillogenesis and cell-mediated collagen reorganization

The extracellular matrix (ECM) is a complex mixture composed of fibrillar collagens as well as additional protein and carbohydrate components. Proteoglycans (PGs) contribute to the heterogeneity of the ECM and play an important role in its structure and function. While the small leucine rich proteoglycans (SLRPs), including decorin and lumican, have been studied extensively as mediators of collagen fibrillogenesis and organization, the function of large matrix PGs in collagen matrices is less well known. In this study, we showed that different matrix PGs have distinct roles in regulating collagen behaviors. We found that versican, a large chondroitin sulfate PG, promotes collagen fibrillogenesis in a turbidity assay and upregulates cell-mediated collagen compaction and reorganization, whereas aggrecan, a structurally-similar large PG, has different and often opposing effects on collagen. Compared to versican, decorin and lumican also have distinct functions in regulating collagen behaviors. The different ways in which matrix PGs interact with collagen have important implications for understanding the role of the ECM in diseases such as fibrosis and cancer, and suggest that matrix PGs are potential therapeutic targets.

Lumican promotes joint fibrosis through TGF-β signaling.

Joint contracture (also known as arthrofibrosis) is a fibrotic joint disorder characterized by excessive collagen production to form fibrotic scar tissue and adhesions within joint capsules. This can severely affect day-to-day activities and quality of life because of a restricted range of motion in affected joints. The precise pathogenic mechanism underlying joint contractures is not fully understood. Lumican belongs to the class II small leucine-rich repeat proteoglycan superfamily, which makes up collagen fibrils in the extracellular matrix. Lumican is ubiquitously expressed in the skin, liver, heart, uterus and articular cartilage and has reported roles in cell migration, proliferation, angiogenesis and Toll-like receptor 4 signaling. Previous research has suggested that lumican is involved in the pathogenesis of several fibrotic diseases. Because joint contracture resembles a fibrotic disease, we aimed to investigate the role of lumican in the development of joint contracture invitro. Here, we showed that protein levels were up-regulated in the fibrotic joint capsule versus control. We observed that lumican significantly enhanced the proliferation, migration and fibroblast-myofibroblast transition of synovial fibroblasts. Moreover, lumican led to increased transcription of alpha-smooth muscle actin, matrix metallopeptidase 9, Collagen I, plasminogen activator inhibitor 1 and transforming growth factor-β invitro. Lumican treatment promoted collagen lattice contraction in a dose-dependent manner as early as 24h after treatment. Thus, our studies reveal that lumican could promote fibroblast-myofibroblast transition and joint contracture.