Background: Bone metastasis is a frequent and debilitating complication of advanced cancer, particularly in breast and prostate cancer, and is driven by complex interactions among tumor cells, bone-resident cells, immune populations, vascular components, and the extracellular matrix. Within this specialized microenvironment, proteoglycans have emerged as key molecular regulators of tumor-bone crosstalk, matrix remodeling, metastatic niche formation, dormancy, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published through 31 May 2026. Search terms included combinations of proteoglycan- and glycosaminoglycan-related concepts, including "proteoglycans," "glycosaminoglycans," "heparan sulfate proteoglycans," "hyaluronan," "heparanase," "syndecans," "glypicans," "perlecan/HSPG2," "versican," and "decorin," with disease- and process-related terms such as "bone metastasis," "extracellular matrix," "tumor-bone crosstalk," "breast cancer," "prostate cancer," "metastatic niche," "osteolytic metastasis," "osteoblastic metastasis," "dormancy," "reactivation," "immune regulation," and "therapy resistance." Original studies, reviews, and translational reports were selected according to their relevance to cell-surface, pericellular, and extracellular proteoglycans in bone metastatic progression. Results: Proteoglycans and associated GAG/ECM axes are implicated in multiple processes involved in skeletal metastasis, including growth factor availability, extracellular matrix organization, osteolytic and osteoblastic niche formation, angiogenesis, immune evasion, metastatic dormancy, reactivation, and therapy resistance. These functions are highly context-dependent and are influenced by proteoglycan localization, core protein structure, glycosaminoglycan composition, sulfation patterns, proteolytic processing, and cellular source. Conclusions: Proteoglycans represent critical molecular nodes in the bone metastatic microenvironment and hold potential as biomarkers, therapeutic targets, and tools for stratifying metastatic niche heterogeneity. Their clinical translation will require validation in human bone metastasis samples, improved models that reproduce the mineralized and immune-rich bone niche, and a clearer distinction between causal mechanisms and correlative associations. Future studies should integrate matrisome profiling, spatial proteomics, single-cell and spatial transcriptomics, glycosaminoglycan omics, degradomics, and three-dimensional bone niche models to define actionable proteoglycan-dependent mechanisms and improve therapeutic targeting of metastatic bone disease.
Autologous minced cartilage offers a single-stage, low-cost alternative to cell therapies for treatment of chondral defects. It is often derived from debrided defects or loose bodies, then minced for reimplantation. However, there is a paucity of knowledge on how mincing cartilage impacts viability and extracellular matrix deposition compared to quality-controlled cell therapies. The purpose is therefore to better characterize minced cartilage by comparing different mincing techniques to isolated cells. Cartilage samples were obtained from fresh human osteochondral allografts (JRF Ortho) and divided into: chondral allograft biopsy (control), manually minced cartilage, arthroscopically minced cartilage, isolated chondrons, and isolated chondrocytes. Samples were embedded in fibrin gels and cultured for 28 days. Staining for viability and histology for collagen and proteoglycan components were performed. Cartilage samples derived from debrided defects or loose bodies were evaluated for sulphated glycosaminoglycans (sGAGs), DNA, and wet weight. At 28 days, viability of chondrons (93.7 ± 2.9%), chondrocytes (94 ± 22%) and manually minced cartilage (79.8 ± 16.2%) were significantly higher than arthroscopically minced cartilage (56.6 ± 15.4%). Over time, isolated cells showed proteoglycan and type II collagen deposition, while minced cartilage groups showed reduced proteoglycan content on histology. Clinical cartilage samples varied >10-fold in wet weight, total DNA, sGAGs/weight, and DNA/weight. This study showed isolated cells have consistently high viability and deposit more proteoglycans over time compared to both minced cartilage groups. Samples typically used for clinical application of minced cartilage can vary over 10-fold in cellularity and proteoglycan content. As consequences for treatment effect are unknown, implementation in clinical practice without quality regulation is not recommended.
The development of regenerative therapies for osteoarthritis and intervertebral disc degeneration requires non-destructive methods to spatiotemporally monitor extracellular matrix (ECM) synthesis. This study aimed to establish a method for the use of bioorthogonal click chemistry for longitudinal and spatially resolved tracking of newly synthesized proteoglycans in cartilaginous tissues, including tools to assess specificity, enable quantification and for future application for noninvasive real-time tracking of ECM production by imaging. Bovine articular cartilage explants, human nucleus pulposus tissue, and human chondrocyte cultures were metabolically labeled using azide-modified N-acetylgalactosamine (Ac4 GalNAz) incorporation with copper-catalyzed and copper-free click chemistry. GAG-specific incorporation was verified by enzymatic digestion with chondroitinase ABC(ChABC) and hyaluronidase (HAse). Sequential labeling with spectrally distinct fluorophores enabled temporal tracking of matrix deposition. Volumetric quantification was performed using ImageJ on confocal microscopy Z-stacks. Near-infrared (NIR) dyes were employed for in vitro and subcutaneous imaging, with photoacoustic imaging used to enhance spatial resolution. Ac4GalNAz demonstrated negligible cytotoxicity at 50 μM in cartilage explants. In tissue explants, metabolic labeling showed high specificity for chondroitin sulfate (CS)-containing proteoglycans, confirmed by ChABC digestion. In contrast, 2D chondrocyte cultures showed ChABC-resistant labeling, suggesting incorporation into membrane-associated glycoproteins. Sequential copper-free labeling distinguished temporally distinct matrix synthesis within the same sample. Using NIR-labels after incorporation, explants were detectable both in vitro and following subcutaneous implantation, with only a moderate loss of signal intensity. Photoacoustic imaging appeared to provide higher spatial resolution, as shown by visualization of implant contours. Bioorthogonal metabolic labeling enables non-destructive, spatially resolved, and quantitative monitoring of proteoglycan synthesis in cartilaginous tissues. Labeling specificity is tissue-context dependent, requiring enzymatic validation for each model system. Integration with NIR fluorescence and photoacoustic imaging provides a foundation for future in vivo applications. Monitoring newly synthesized extracellular matrix (ECM) in cartilaginous tissues is a critical challenge in regenerative medicine for osteoarthritis and intervertebral disc degeneration. Building on prior work demonstrating metabolic labeling feasibility in cartilage, this study substantially advances the field by establishing quantitative, spatiotemporally resolved proteoglycan tracking across multiple clinically relevant model systems, including nucleus pulposus tissue. We introduce volumetric 3D quantification of newly synthesized ECM from confocal z-stacks, sequential temporal labeling to distinguish matrix deposition at different timepoints, and near-infrared and photoacoustic imaging enabling subcutaneous detection. Critically, we identify model-dependent labeling specificity, highlighting the need for validation in each model. Together, these advances provide a comprehensive framework for non-destructive monitoring of ECM regeneration with direct translational potential.
Hyaluronan and proteoglycan link protein 1 (HAPLN1) is a glycoprotein that stabilizes hyaluronan-proteoglycan complexes and maintains extracellular matrix integrity. Two protein forms of HAPLN1 have been reported; however, their structural and functional distinctions remain poorly understood. Here, we characterized two recombinant human HAPLN1 (rhHAPLN1) forms expressed in CHO cells using in-gel glycomic and glycoproteomic analyses with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and nano-LC-MS/MS. SDS-PAGE resolved two protein forms: rhH-1 (∼44 kDa, 76.3%) and rhH-2 (∼40 kDa, 23.7%). Both forms exhibited identical amino acid sequences and shared two N-glycosylation sites (Asn6 and Asn41), as confirmed by analysis of in-gel tryptic glycosylated and deglycosylated peptides. A total of 22 and 15 N-glycans were identified in rhH-1 and rhH-2, respectively. At Asn6, rhH-1 contained highly branched, sialylated N-glycans (50.0%, normalized to 100% for each site), whereas rhH-2 showed low occupancy (3.7%) with non-sialylated N-glycans. In contrast, Asn41 exhibited nearly identical profiles in both forms, comprising predominantly bi-antennary, highly sialylated N-glycans (84.0% in rhH-1 and 83.9% in rhH-2). Mild formic acid preserved tri/tetra-sialylation during N-glycopeptide recovery, and higher-energy collisional dissociation at two normalized collision energies improved N-glycan/peptide fragmentation for confident N-glycopeptide identification. Functional assays demonstrated that rhH-1 displayed 7.5-fold higher linking potency (EC50 values of 133.5 ng/mL for rhH-1 and 994.8 ng/mL for rhH-2) toward hyaluronan and proteoglycans than rhH-2, while both showed similar efficacy (Emax). This study provides the first comprehensive structural and functional comparison of sequence-identical rhHAPLN1 forms, revealing distinct site-specific N-glycosylation associated with differences in potency.
In immune cells, heparin was first identified in mast cells in the 1940s, followed by the discovery of heparan sulfate in lymphocytes and granulocytes during the 1970s and 1980s. Subsequent decades of research have revealed how heparan sulfate and heparin, conjugated to core proteins as heparan sulfate proteoglycans (HSPGs), act as versatile modulators of immune function. It is now known that HSPGs are expressed by virtually all leukocytes and bind hundreds of immune mediators, including cytokines, proteases, growth factors, antimicrobial peptides, and extracellular matrix (ECM) components. HSPGs on leukocyte surfaces and within intracellular granules, as well as those on non-immune cells and within the ECM, shape immune cell development and responses to both endogenous and exogenous threats. Because immune activity must be tightly controlled to prevent collateral tissue damage, HSPGs play critical modulatory roles-facilitating, competing, protecting, presenting, or allosterically regulating immune factors. Consequently, mutations in HSPG core proteins and heparan sulfate biosynthetic enzymes, or dysregulation of HSPG-mediated immune interactions, contribute to diverse pathologies, including primary immunodeficiencies, autoimmune disease, infection, inflammatory tissue injury, allergy, and cancer. This review will highlight key mechanisms through which HSPGs regulate the development and function of major immune cell types.
Painful intervertebral disc degeneration is a leading cause of chronic low back pain. Proteolytic cleavage fragments of extracellular matrix components, particularly aggrecan and small leucine-rich proteoglycans (SLRPs), may act as endogenous danger signals activating inflammatory pathways. To determine whether proteolytic fragments of aggrecan and SLRPs correlate with disc degeneration severity and Toll-like receptor-2 (TLR-2) mediated inflammation. Human disc tissues were analysed from 20 non-degenerated cadaveric controls (Thompson Grades 1-2) and 35 patients with painful degeneration (Pfirrmann Grades 3-5). Western blotting assessed fragmentation of aggrecan and SLRPs (decorin, biglycan, lumican, fibromodulin, chondroadherin). Immunofluorescence localized these molecules in disc sections. Disc cells were cultured under four conditions: unstimulated controls, TLR-2 agonist Pam2CSK4-stimulated controls, cells extracted from degenerated discs, and those treated with the TLR-2 antagonist MMG-11. Cytokine profiles were determined using antibody array. Fragmented peptides of aggrecan and SLRPs (22-45 kDa) were predominantly detected in Pfirrmann Grades 4 and 5 discs. TLR-2 expression was significantly higher in degenerated disc cells versus controls (P < 0.001), further upregulated by Pam2CSK4 and attenuated by MMG-11. Cytokine analysis revealed marked pro-inflammatory shifts in patient discs (interleukin [IL]-6 ↑1.37×, IL-8 ↑1.30×, IL-1β ↑1.25×), while control discs exhibited an anabolic profile with elevated expressions of growth factors (TGF-β, EGF, VEGF). Aggrecan and SLRP fragments were observed alongside TLR-2 mediated inflammatory responses in advanced disc degeneration, suggesting a potential association with tissue catabolism. Targeting TLR-2 signaling may warrant further investigations as a potential therapeutic strategy for painful disc disease.
We determined spatial/temporal expression of keratan sulfate proteoglycan (KS) in the developing cerebellar system, fasciculi, and dysgeneses. KS is an extracellular molecule secreted by astrocytes that forms a template for neuroblastic migration and axonal fascicles and creates perineural nets. We studied KS immunoreactivity in cerebellar cortex, deep cerebellar, inferior olivary, red and pontine nuclei, and white matter of 25 control human fetuses 12-41 weeks gestation and 16 cerebellar dysgeneses. Dentate, inferior olivary, and red nuclei were nonreactive at all ages. Pontine nuclei were positive from the early second trimester. Bergmann glia and cerebellar white matter pathways were nonreactive throughout fetal and postnatal life. Transitory KS septa demarcated the vermal/hemispheric boundary. KS was not expressed in Dandy-Walker or Chiari malformations, cerebellar hypoplasia, heterotopia, pontocerebellar hypoplasia, or rhombencephalosynapsis. Axonal fascicles caudal to the internal capsule did not exhibit KS. The absence of hindbrain KS contrasts with strong forebrain immunoreactivity. Lack of KS expression in typically developing cerebellum and associated brainstem nuclei (except pontine), or in dysgeneses, implies that KS does not contribute to cerebellar system malformation pathogenesis. Transitory KS septa define early vermal margins similar to neuromeric segmentation septa. The intense KS template of the internal capsule does not extend caudally into brainstem fascicles.
Ovarian cancer is one of the most lethal cancers in women worldwide. To be able to offer successful treatment and improve the prognosis, knowledge of factors influencing the tumor microenvironment is indispensable. In this context, the influence of the extracellular matrix on tumor progression is increasingly recognized. Of note, preclinical data in cell line and animal models have suggested that several members of the small leucine-rich proteoglycan (SLRP) family are mechanistically involved in the regulation of tumor progression. We hypothesized that dysregulation of SLRP expression may have a prognostic value in ovarian cancer. To distinguish whether this expression is altered in the cells themselves or in the extracellular matrix, quantitative Real-Time PCR was performed on ovarian cancer cell lines and complemented by analysis of CCLE datasets. We used Kaplan-Meier survival curves to investigate whether a high or low mRNA expression influences the survival of ovarian cancer patients. Finally, the interactions of the SLRPs were investigated using a STRING analysis. We demonstrated the potential beneficial effect of a low mRNA expression of most SLRPs on the prognosis of serous ovarian cancer. STRING analysis revealed interactions with other proteins already known to influence tumor behavior and metastasis of various carcinomas. These findings suggest that SLRPs may be involved in ovarian cancer biology and could represent candidates for further mechanistic investigation. However, their potential relevance for therapeutic strategies, including treatment response, requires additional functional validation.
Cartilage extracellular matrix (ECM), a hydrated collagen II-aggrecan composite, undergoes dynamic turnover during both normal homeostasis and disease-associated remodeling. This study elucidates a crucial role for decorin in promoting the retention and stability of nascent aggrecan within this matrix. By applying bio-orthogonal click-labeling, we demonstrate that loss of decorin accelerates the release of nascent aggrecan under both physiological and inflammatory conditions, without affecting its preferential localization to the pericellular matrix. Conversely, supplementation with exogenous decorin mitigates inflammation-induced loss of nascent aggrecan, supporting its potential as a therapeutic target. At the molecular level, decorin exhibits strong binding affinity for aggrecan, and enhances aggrecan-aggrecan and aggrecan-collagen II interactions, reinforcing its direct role in integrating cartilage matrix constituents. Also, by binding to collagen II, decorin stiffens the collagen II fibril network, thereby strengthening the confinement effect that limits the diffusive loss of entrapped aggrecan. Notably, decorin does not alter chondrocyte transcriptomic profiles in vivo, emphasizing its primary role in maintaining matrix integrity through biophysical mechanisms rather than cell signaling. Together, these findings provide a mechanistic foundation for developing decorin-based biomaterials or gene therapies aimed at preserving or regenerating the cartilage matrix for improved outcomes in osteoarthritis. STATEMENT OF SIGNIFICANCE: Development of effective cartilage repair strategies is challenged by the limited understanding of molecular events that regulate the dynamic turnover and degenerative changes of cartilage extracellular matrix. This study shows that decorin, a small proteoglycan, promotes the retention and stability of nascent aggrecan within both normal and degenerative cartilage matrix by augmenting the integration between collagen II and aggrecan molecules and strengthening the collagen II fibril network. In turn, exogenous decorin mitigates the accelerated loss of nascent aggrecan instigated by inflammatory stimulation. Collectively, these findings establish decorin as a therapeutic target for preserving cartilage matrix integrity and improving osteoarthritis intervention.
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Glioblastoma multiforme (GBM), due to its complex and highly heterogeneous nature, remains one of the deadliest cancers in the world. However, advances in targeted therapy offer hope for improved GBM treatment through extensive research into receptor-mediated targeting approaches that exploit receptors overexpressed on the surface of GBM cells, including interleukin-13 receptor alpha 2 (IL-13Rα2), transferrin receptor (TfR), receptor tyrosine kinases (RTKs), and integrins. Nanoparticles such as liposomes, lactoferrin-based specialized nanocarriers, and gold nanoparticles functionalized with targeting ligands including Pep-1L, lactoferrin, and RGD peptides, and loaded with anticancer drugs such as temozolomide, gefitinib, and epirubicin, are being explored for targeted GBM therapy. These approaches have demonstrated promising preclinical outcomes, with several formulations in early-phase clinical trials to evaluate safety, pharmacokinetics, and therapeutic efficacy. Certain receptors, including periostin (POSTN) and chondroitin sulfate proteoglycan-4 (CSPG4), involved in tumor invasion, glioma stemness, and therapeutic resistance, remain relatively underexplored, presenting opportunities for further research. Despite these advances, clinical translation remains limited by nanoparticle-associated cytotoxicity and off-target effects. This highlights the need for future research focused on developing biodegradable and biocompatible nanomaterials, along with optimized ligand-guided designs, to improve safety and enhance translational feasibility in glioblastoma therapy. Literature search Methodology: [PubMed and Google Scholar; 2006-2026]. Glioblastoma is a difficult type of brain tumor that is hard to treat, as most of the drugs are incapable of crossing the blood-brain barrier (BBB) and don’t reach the tumor. Scientists are currently working on nanotechnology-based therapies to enhance the capability of delivering drugs directly to cancer (tumor) cells by using nanoparticles. One potential approach is to design the nanoparticles to identify certain tumor cell receptors. Several receptors have been discussed in the review article, which include interleukin-13 receptor alpha 2 (IL-13Rα2), transferrin receptor (TfR), integrins, and receptor tyrosine kinases (RTKs), that serve as a Docking station to the drug-loaded nanoparticles, and they assist the drugs in targeting cancer cells without damaging healthy brain cells. Scientists are now capable of engineering advanced nanoparticles that respond to the tumor microenvironment, thus releasing drugs only when required. Current research emphasizes that combining conventional therapies with receptor-targeted nanoparticles may slow tumor development and increase patients’ survival outcomes. Researchers have developed a new area of interest as it involves receptor POSTN and CSPG4 as emerging targets for improving future glioblastoma therapies. Altogether, receptor-guided nanotechnology represents a significant advancement toward safe and personalized treatment of glioblastoma, which adds value to survival and quality of Life for patients suffering from this challenging brain cancer.
People with Marfan syndrome (MFS) exhibit a high incidence of hip joint pain and earlier onset of osteoarthritis than those without MFS. Imaging-related biomarkers of hip joint health that provide an earlier indication of hip cartilage degeneration in the MFS population have yet to be assessed. We sought to determine whether people with MFS exhibit biochemical alterations of proteoglycan content and collagen structure within the hip joint cartilage compared to individuals without MFS as documented by quantitative magnetic resonance imaging (MRI) including both T1ρ and T2 mapping. Fourteen individuals with MFS and 14 healthy, asymptomatic controls matched for age, sex, and body mass index underwent radiographic imaging and unilateral hip quantitative MRI including both T1ρ and T2 mapping to evaluate cartilage proteoglycan content and collagen structure. People with MFS showed significantly higher T1ρ values in the anterior superior acetabular cartilage compared to the asymptomatic controls. No significant between-group differences were noted in the femoral T1ρ values or in any of the T2-related values. This cross-sectional, observational study found elevated anterior superior acetabular cartilage T1ρ values, indicating a lower proteoglycan content within this specific sub-region, in individuals with MFS. The anterior superior acetabular cartilage may be prone to degeneration and may contribute to the high rates of early onset osteoarthritis observed in the MFS population. Our results suggest T1ρ cartilage imaging may be a potential biomarker of early cartilage degradation in the MFS population. Clinically, T1ρ imaging may allow for better informed decisions regarding interventional timing to prevent the onset and progression of hip osteoarthritis in individuals with MFS. Level III, prognostic study.
Prediction of cartilage structural properties through MRI could allow earlier detection of joint pathologies, such as osteoarthritis. Bovine patellar cartilage samples (n = 12) were imaged using magnetic resonance fingerprinting, followed by histological examination of proteoglycan content and collagen fiber anisotropy. The relaxation time maps and raw signal data were then used for training Gaussian process regression (GPR) models to predict the histology results. Proteoglycan content was predicted by the GPR models with high accuracy (median r = 0.81, σ = 0.08 and NRMSE = 11.7%). Predictions performed using raw MRF data outperformed those done using qMRI maps. Collagen fiber anisotropy predictions found only weak correlation (median r = 0.40, σ = 0.25 & NRMSE = 26.4%) and no significant difference was seen between models trained on raw MRF or relaxation time maps. These findings indicate that noninvasive prediction of proteoglycan content in cartilage from MRF measurements using a 3 T clinical scanner is feasible, holding promise for future clinical applications. Collagen fiber anisotropy could not be reliably estimated with the current setup. GPR-based prediction models were found to outperform reference linear models using the same prediction data.
The extracellular matrix plays critical roles in orchestrating cell communication and behaviors in response to various extracellular signals. It is a complex network composed of proteins and polysaccharides, whose individual and synergistic roles in cellular signaling, structural integrity, and tissue homeostasis remain active areas of investigation. Here, we find that in the developing cerebral cortex, distinct glypicans, which are heparan sulfate proteoglycans, present very precise and complementary expression patterns. More precisely, GPC4, which is expressed in cortical progenitors, promotes their proliferation and the generation of intermediate progenitors, whereas neuronal GPC2 acts as a brake on radial neuronal migration. The diverse biological functions of these proteoglycans are widely regarded as being intrinsically tied to their glycosaminoglycan (GAG) chains. Strikingly, we found that these effects are mediated only through glypican core proteins, rather than their heparan sulfate glycosylations. We found that the only difference between them is in their C-terminal disordered regions, which have a high density of charged residues. GPC2 is strongly basic, whereas GPC4 is acidic. Together, our findings highlight how specific proteoglycan protein cores are required to drive sequential cellular responses during cortical development in a glycosylation independent manner.
Heparan sulfate proteoglycans (HSPGs) are essential cell surface and extracellular matrix glycoconjugates that mediate diverse biological processes through interactions between their heparan sulfate (HS) chains and extracellular ligands. While HS sulfation patterning is known to dictate ligand specificity, how cells control HS assembly to regulate these interactions remains incompletely understood. To systematically identify genetic modifiers of HS-protein interactions, we performed genome-wide CRISPR activation (CRISPRa) screens in HEK293T cells using binding of antithrombin (AT), which selectively recognizes 3-O-sulfated HS motifs, or the N-sulfation-specific antibody 10E4 as functional readouts. Strikingly, the screens revealed proteoglycan core proteins as key modulators of HS function. In particular, syndecan-1 (SDC1) emerged as a preferential enhancer of AT binding compared to other syndecan family members. Targeted upregulation of syndecan family members increased total HS levels, but only SDC1 enhanced AT binding. Structural and enzymatic analyses demonstrated that SDC1-associated HS chains contain elevated 6-O-sulfation and serve as superior substrates for 3-O-sulfotransferases relative to SDC2-associated HS chains. Additionally, SDC1 exhibited slower cell surface recovery, which was blocked by cycloheximide treatment, consistent with extended trafficking and biosynthetic processing. Overall, these findings indicate that proteoglycan core protein identity influences HS sulfation patterning and ligand-binding specificity and trafficking kinetics may contribute to core protein-dependent regulation of HS modification.
Hyaluronan and proteoglycan link protein 1 encodes HAPLN1, a critical structural protein in the extracellular matrix (ECM), essential for maintaining tissue architecture and integrity. HAPLN1 mediates stable interactions between hyaluronan and proteoglycans, crucial elements of the ECM that confer structural stability, elasticity, and functional regulation to connective tissues. Aberrations in HAPLN1 expression or function have been implicated in various pathological conditions, including inflammation and tumorigenesis in humans and skeletal dysplasias in mice. To the best of our knowledge, HAPLN1 has not been implicated in human skeletal dysplasia. Herein, we report a novel homozygous missense variant in HAPLN1 in four individuals from an extended consanguineous Kuwaiti family, co-segregating with a skeletal dysplasia phenotype. Affected individuals presented with shortened long bones of both upper and lower limbs, square-shaped iliac wings, narrowed sciatic notches, flattened acetabular roofs, progressive narrowing of the lumbar interpedicular distance with widened intervertebral disc spaces, and short, stubby metacarpal bones. Our findings identify HAPLN1 as a candidate gene underlying a newly described autosomal recessive skeletal dysplasia.
Pulmonary fibrosis is a chronic progressive lung disease characterized by extensive fibrosis and poor prognosis, highlighting the urgent need for novel therapeutic strategies. This study aims to elucidate the role of the small proteoglycan proline/arginine-rich end leucine-rich repeat protein (PRELP), evaluate the protective potential of recombinant PRELP protein, and investigate its underlying molecular mechanisms. RNA in situ hybridization was performed on lung sections prepared from control subjects and patients with idiopathic pulmonary fibrosis (IPF). In mouse experiments, we established a bleomycin (BLM)-induced lung fibrosis model using PRELP knockout mice and assessed the extent of fibrosis. Furthermore, we administered recombinant PRELP protein via the airway in wild-type mice with BLM-induced fibrosis to evaluate its effects. In vitro experiments were conducted to investigate the role of PRELP in alveolar epithelial cells and fibroblasts. In human lungs, PRELP expression was mainly detected in stromal regions and partly in type 2 alveolar epithelial cells. Furthermore, PRELP was broadly expressed in alveolar areas of controls but was markedly reduced in the alveolar region and localized to vessel walls in IPF patients. In mouse experiments, fibrosis was more severe in PRELP knockout mice after BLM intratracheal administration than in wild-type mice. Notably, prophylactic trans-airway administration of recombinant PRELP suppressed BLM-induced fibrosis in wild-type mice in vivo. In vitro experiments revealed that PRELP suppresses the acquisition of mesenchymal traits and enhances the maintenance of epithelial cell function in epithelial cells, while inhibiting the migratory ability of fibroblast cells. Mechanistically, PRELP suppressed fibrotic changes in epithelial cells not only through the transforming growth factor-beta (TGF-β) pathway but also via Receptor for advanced glycation end products (RAGE)/ Diaphanous 1 (DIAPH1)/ Yes-associated protein (YAP) signaling axis. The small proteoglycan PRELP plays a pivotal role in a mouse model of pulmonary fibrosis by suppressing the upregulation of mesenchymal markers, reinforcing epithelial cell function, and inhibiting fibroblast migration. Notably, prophylactic trans-airway administration of recombinant PRELP protected against pulmonary fibrosis, indicating that PRELP may be a promising novel protective agent for this disease.
Breast cancer remains a leading cause of morbidity and mortality among women worldwide, necessitating in-depth research into its molecular mechanisms to improve prognosis and treatment strategies. This study investigates the expression profile and functional role of heparan sulfate proteoglycan Syndecan-1 (SDC1) in breast cancer progression, with a focus on its downstream signaling pathways. Utilizing bioinformatics analysis of datasets from the GEO and TCGA databases, we identified significantly elevated SDC1 expression in breast cancer tissues compared to normal counterparts, correlating with advanced tumor stage, lymph node metastasis, and poor survival outcomes. Clinical sample validation through RT-qPCR and Western blot confirmed SDC1 overexpression in breast cancer tissues and cell lines. Functional experiments, including SDC1 knockdown via lentiviral infection, revealed that reduced SDC1 expression markedly impairs breast cancer cell proliferation, migration, and angiogenesis, as evidenced by CCK-8, EdU, wound healing, Transwell, and tube formation assays. Mechanistically, transcriptome sequencing and Western blot analysis demonstrated that SDC1 knockdown significantly suppressed the phosphorylation of key MAPK pathway components (ERK1/2, JNK, and p38). Rescue experiments using the MAPK agonist C16-PAF effectively reversed the inhibitory effects of SDC1 knockdown on cell proliferation, migration, and angiogenesis. Furthermore, in vivo xenograft models confirmed that SDC1 knockdown suppressed tumor growth and reduced microvessel density, while C16-PAF treatment partially reversed these effects. Collectively, our findings demonstrate that SDC1 promotes breast cancer progression by activating the MAPK signaling pathway, highlighting SDC1 as a potential prognostic biomarker and therapeutic target in breast cancer.
Camptodactyly-arthropathy-coxa vara-pericarditis syndrome is a rare autosomal recessive disorder caused by loss-of-function variants in the proteoglycan 4 gene, which encodes lubricin. It is frequently misdiagnosed as juvenile idiopathic arthritis, leading to prolonged immunosuppressive therapy. We report two unrelated boys born to consanguineous parents who presented with progressive large-joint swelling and were initially diagnosed with juvenile idiopathic arthritis. Both received multiple disease-modifying and biologic agents without clinical response. Inflammatory markers remained persistently normal, and radiographs showed preserved joint spaces without erosive changes. Camptodactyly developed later in the disease course. One patient developed pericardial effusion and showed a reduced bone mineral density on dual-energy X-ray absorptiometry with limited hip motion and acetabular changes; the other patient showed only a qualitative radiographic image of a reduced bone mineral density but was not confirmed by dual-energy X-ray absorptiometry. Whole-exome sequencing identified a previously reported homozygous frameshift variant in proteoglycan 4 gene (c.2208del; p.Thr737ProfsTer175) in the first patient and a homozygous nonsense variant (c.4104T > A; p.Tyr1368Ter) in the second which was absent from ClinVar and Varsome (accessed April 2026) and it was classified as pathogenic by ACMG/AMP. Camptodactyly-arthropathy-coxa vara-pericarditis syndrome should be considered in children with non-inflammatory arthropathy unresponsive to immunosuppressive therapy. The recognition of the broader phenotypic burden including reduced bone mineral density supports the need for a standard method to assess bone health beyond the classical tetrad approach. Early whole-exome sequencing can shorten the diagnostic journey and redirect management toward appropriate supportive care.
Background and Objectives: Temporomandibular disorders (TMDs) encompass a broad spectrum of functional and structural abnormalities of the temporomandibular joint (TMJ). Conventional diagnostic tools, although essential, often fail to capture the underlying biochemical mechanisms driving disease progression. Synovial fluid (SF), by virtue of its direct proximity to intra-articular tissues, represents an accessible biological matrix for identifying molecular signatures of inflammation, cartilage degradation, lubrication failure, oxidative stress, and angiogenic activation. The objective of this review is to synthesize current evidence on SF proteomics in TMD and evaluate its potential translational value in precision medicine. Materials and Methods: A narrative review of the literature was conducted on PubMed to identify human studies focused on SF proteomic and biochemical biomarkers in TMD. Eligible studies included original research articles assessing SF composition in relation to specific TMJ pathologies, diagnostic categories, or clinical phenotypes. Extracted data included study design, sample characteristics, analytic methodology, biomarkers investigated, and key findings. Google Gemini (Google LLC, Mountain View, CA, USA) was used as an AI-assisted tool to support language editing and manuscript writing during the preparation of this article. The use of this tool was limited to linguistic refinement; all scientific content, data interpretation, and conclusions were formulated and verified by the authors. Results: Across the analyzed studies, TMD phenotypes-particularly disc displacement with or without reduction (DDwR, DDwoR) and osteoarthritis (OA)-were characterized by consistent alterations in cytokines (IL-1β, IL-6, IL-8, TNF-α), extracellular matrix (ECM) components (aggrecan, glycosaminoglycans (GAGs), decorin, MMP-2, MMP-9), lubrication molecules (lubricin/PRG4), oxidative stress mediators (myeloperoxidase (MPO), nitric oxide (NO), glutathione peroxidase (GPX)), adipokines (chemerin, resistin, adiponectin), and angiogenic factors (vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2)). Recent liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses further revealed phenotype-specific protein clusters and pathways related to inflammation, ferroptosis, hypoxia signaling, and proteoglycan metabolism. Conclusions: Current evidence suggests that SF proteomics and multi-analyte biomarker profiling offer a promising, hypothesis-generating approach for understanding the biological mechanisms underlying TMD. The integration of proteomic, metabolic, and inflammatory markers holds future potential for diagnostic panel development; however, prospective clinical validation is still required before SF-based molecular profiling can be implemented as a precision medicine tool in TMJ disorders.