Gastric cancer remains a leading cause of cancer-related mortality worldwide, and effective preventive or therapeutic vaccines are still lacking. WNT1‑inducible signalling pathway protein 1 (WISP1/CCN4) is a secreted matricellular protein that is overexpressed in gastric tumours and associated with poor prognosis, making it a promising immunotherapy target. We aimed to design a multi‑epitope protein vaccine candidate targeting WISP1 using an immunoinformatics workflow. We predicted linear B‑cell epitopes from WISP1 and filtered them for antigenicity, non-allergenicity, and non-toxicity. High‑scoring MHC class I and class II T‑cell epitopes with broad HLA coverage were then selected. The final construct combined validated B‑ and T‑cell epitopes with appropriate linkers and a TLR‑agonist adjuvant to enhance immunogenicity. Physicochemical profiling indicated that the construct is stable, soluble, hydrophilic and antigenic, with no predicted allergenicity or toxicity. Secondary and tertiary structures were modelled, refined and validated, revealing proper folding and favourable stereochemical quality. Molecular docking showed strong binding to innate immune receptors, particularly TLR4, and molecular dynamics simulations confirmed stable receptor-vaccine interactions with low structural deviation. Binding‑free energy analysis further supported these results. Immune simulations predicted robust primary and secondary immune responses characterised by sustained IgG/IgM production, increased IFN‑γ and IL‑2, and activation of memory B and T cells. Codon optimisation and in‑silico cloning suggested feasibility for experimental expression. These results indicate that the proposed WISP1 multi‑epitope vaccine is antigenic, safe, structurally stable and capable of eliciting broad humoral and cellular immune responses in silico. This work provides a testable candidate for experimental validation and highlights secreted CCN family proteins as novel targets for gastric cancer vaccines.

Keratinocyte stem cells are essential for maintaining epidermal homeostasis and enabling efficient tissue repair. Regulation of their self-renewal and differentiation is critical, as its disruption can impair regeneration and drive pathological conditions such as chronic wounds and cancer. We previously identified the matricellular protein Mindin as a key regulator of keratinocyte stemness through its interaction with the αMβ2 (CD11b/CD18) integrin and subsequent activation of the transcription factor STAT3. However, the mechanism connecting Mindin and integrin at the cell surface to the intracellular activation of STAT3 remained undefined. We employ biochemical and imaging analysis along with molecular dynamics simulations to dissect Mindin-integrin-STAT3 signalling in primary mouse keratinocytes. Stemness of epidermal keratinocytes are assessed using bulk RNA sequencing, quantitative PCR, and cell-based assays. Our work demonstrates that the F-Spondin domain of Mindin constitutes the minimal integrin-binding module required to initiate downstream signalling. F-Spondin binding to the integrin at the plasma membrane does not elicit the full activation state of the integrin. Instead, it promotes Src-kinase dependent endocytosis of the integrin receptor to the early endosomes. Analysis of integrin conformational dynamics reveals that the acidic environment of early endosomes is essential to achieve a signalling-competent state. This mechanism extends to pathological contexts, as we demonstrate a requirement for endocytosis in activating STAT3 signalling and preserving stem-like properties in a cancer stem cell model. These findings highlight a previously unrecognized layer of spatial control in integrin signalling, confirming endosomal trafficking as a critical determinant of stem cell behaviour and offering new conceptual and therapeutic opportunities across regenerative biology and cancer.

Pulmonary arterial hypertension (PAH) is a complex progressive disease associated with high morbidity and mortality. Circulating serum biomarkers have the potential to optimize diagnosis and prognosis in PAH. The cellular communication network (CCN) protein family is a group of similarly structured matricellular proteins with many roles ranging from fibrosis to malignancy. Individual CCN proteins have been associated with PAH in previous studies, but no study has evaluated multiple CCN proteins as potentially relevant biomarkers in PAH. This study sought to establish associations using the circulating concentrations of measurable CCN proteins and PAH diagnosis, severity, outcomes, and other biomarkers. Serum levels of CCN1, CCN2, CCN3, and CCN6 were measured utilizing 225 patients from the PAH Biobank (PAHBiobank) with available hemodynamic data and 40 control samples. Serum levels of CCN1, 2, 3, and 6 proteins were significantly increased in PAH compared to controls. CCN1, CCN2, and CCN3 were associated with a lower 6-min walk distance. CCN2 and CCN3 were also associated with worse New York Heart Association Functional Class. Higher CCN2 and CCN3 levels correlated with higher levels of Endostatin and NT-proBNP. CCN6 was not significantly associated with any hemodynamic or clinical variables in the PAH cohort. Our results suggest that multiple CCN proteins are increased in PAH and that CCN2 and CCN3 have the most potential as novel biomarkers in PAH.

Intestinal ischemia-reperfusion (IR) injury presents as a severe condition characterized by microvascular dysfunction, epithelial barrier disruption, and systemic inflammatory responses, for which effective targeted therapies remain limited. Accumulating evidence indicates that pathological accumulation of extracellular matricellular proteins within ischemic microvascular niches critically amplifies oxidative stress and tissue damage during reperfusion. Here, we report a peptide-functionalized, biodegradable nanoplatform designed to selectively recognize and scavenge extracellular thrombospondin-1 (TSP-1) in ischemic intestinal peripheral vessels. LSKL-functionalized PEG-PLGA nanoparticles (LSKL/NPs) exhibit high affinity and stability in binding TSP-1 and preferentially accumulate within injured intestinal microvasculature following ischemia-reperfusion. By efficiently depleting pathological TSP-1, LSKL/NPs suppress TSP-1-mediated oxidative stress signaling, attenuate endothelial and epithelial apoptosis, and preserve vascular and intestinal barrier integrity. As a consequence, intestinal inflammation is markedly reduced, bacterial translocation is limited, and systemic inflammatory responses are alleviated, resulting in significant protection against distant organ injury. Importantly, LSKL/NPs demonstrate favorable biocompatibility and biosafety in vivo. Collectively, this study establishes a biomaterial-mediated extracellular protein scavenging strategy that mitigates intestinal ischemia-reperfusion injury by targeting pathological TSP-1 accumulation within peripheral vessels, offering a versatile and translationally promising nanotherapeutic paradigm for ischemic tissue protection. STATEMENT OF SIGNIFICANCE: This study reports a peptide functionalized, biodegradable PEG PLGA nanoparticle platform (LSKL/NPs) designed to scavenge extracellular thrombospondin 1 (TSP 1) for intestinal ischemia reperfusion injury (IRI). This focus is important because intestinal IRI is a devastating condition with limited effective therapies, and pathological extracellular mediators within ischemic microvascular niches remain insufficiently targeted. The work is significant because it defines a biomaterial driven mechanism in which LSKL/NPs preferentially accumulate in injured intestinal microvasculature and sequester extracellular TSP 1, thereby suppressing endothelial cell apoptosis and oxidative stress signaling, preserving endothelial and epithelial integrity, restoring barrier function, and reducing systemic inflammation and distant organ injury. Overall, this study establishes extracellular protein scavenging enabled by clinically validated, biodegradable materials as a generalizable therapeutic paradigm for ischemic tissue injury.

SPARC in Musculoskeletal Tissues: Linking Matrix Assembly to Disease.

Renal tubulointerstitial fibrosis (TIF) is a central pathological feature driving the progression of chronic kidney disease (CKD) toward end-stage renal failure. Despite advances in understanding fibrotic mechanisms, effective anti-fibrotic therapies remain limited. Here, we identify SPARC, a matricellular protein expressed in proximal tubular epithelial cells (PTECs), as a key mediator of TIF. SPARC expression strongly correlates with fibrosis severity in both human CKD biopsies and murine models of unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI). Genetic ablation of Sparc markedly attenuates renal fibrosis in these models. Mechanistically, SPARC stabilizes DOT1L protein, enhancing H3K79 di-methylation (H3K79me2) and promoting fibrotic changes in PTECs. This process is orchestrated by the acetyltransferase CBP, whose regulation of DOT1L stability depends on MEK-ERK signaling. The SPARC-CBP-DOT1L axis thus defines a previously unrecognized epigenetic pathway driving renal fibrosis. Our findings establish SPARC as a critical driver of TIF and highlight the SPARC-CBP-DOT1L signaling cascade as a promising therapeutic target for halting fibrotic progression in CKD.

Sparc-driven p62-dependent mitochondrial oxidative stress exacerbates myocardial ischemia and is attenuated by ginsenoside CK.

Maternal serum SPARCL-1 levels in preeclampsia: Diagnostic performance by onset subtype.

Atrial fibrillation and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2+ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis, inflammation, and atrial fibrillation. Here we developed an antibody-siRNA conjugate (ARC) drug candidate to silence Spp1. The ARC relies on an anti-TREM2 antibody for delivering Spp1-targeted siRNA to a pathogenic macrophage subset that expands in human atrial fibrillation. The ARC preferentially targeted atrial TREM2+ macrophages with limited uptake by other immune or stromal cells of the heart. We observed efficient silencing of the target gene in human myocardium and in mice, where it reduced pro-fibrotic fibroblast activation and atrial fibrosis. Four weeks of systemic ARC treatment suppressed inducible atrial fibrillation in mice exposed to clinically prevalent risk factors. These results suggest that macrophage subset targeting offers a viable immunomodulatory strategy for atrial fibrillation.

Musculoskeletal tissue interfaces (TIs), including osteotendinous, myotendinous, and osteochondral junctions, are specialized regions that enable effective force transmission, mechanical stability, and long-term tissue integration. These interfaces are defined by gradients in cellular composition, extracellular matrix (ECM) organization, and mechanical properties, and their maintenance relies in part on tightly regulated cell-matrix interactions. Beyond structural ECM components, matricellular proteins such as Secreted Protein Acidic and Rich in Cysteine (SPARC), thrombospondins, osteopontin, periostin, and tenascins have emerged as critical modulators of interface biology by shaping ECM assembly, mechanotransduction, and adaptive cellular responses to load. SPARC has been shown to impact on collagen fibrillogenesis, ECM organization, and cell-matrix signaling across multiple musculoskeletal tissues. It is increasingly recognized as a regulator of load-bearing musculoskeletal tissue interfaces, where its dysregulation drives maladaptive remodeling marked by fibrosis, ectopic mineralization, and reduced regenerative capacity across pathologies such as tendinopathy, intervertebral disc disease, and osteoarthritis. This mini-review summarizes current knowledge on matricellular regulation at musculoskeletal tissue interfaces, with a focus on SPARC, integrating evidence from genetic models to investigate its role in interface homeostasis, mechanical adaptation, and pathological remodeling.

Periostin (Postn) is a matricellular protein that plays a crucial role in cardiac fibrosis following myocardial infarction (MI). However, the role of Postn in infarct healing to date has been derived from experiments conducted exclusively on male animals, leaving its sex-specific functions unaddressed. Thus, we investigated the sex-specific role of Postn in acute wound healing and extracellular matrix (ECM) remodeling post-MI using a Postn knockout (KO) mouse model. Survival analysis revealed increased mortality in male Postn KO mice compared with that of females post-MI. qPCR analysis of the infarct scar showed that Postn was required for the increased expression of structural collagen (Col1a1 and Col3a1), collagen fibrillogenesis (Fmod), collagen stabilization (Lox), collagen synthesis (Plod2), and alpha-smooth muscle actin (Acta2) genes in males, whereas in females, the regulation of these genes occurred independently of Postn post-MI. We note that fibromodulin protein levels were higher in female Postn KO mice than in males, suggesting a putative protective role. Transcriptomic analysis revealed distinct gene expression patterns between sexes and phenotypes, with male Postn KO infarct scars showing the greatest dysregulation of genes, characterized by increased expression of ECM-related genes and suppressed mitochondrial-related gene expression, whereas female Postn KO infarct scars exhibited increased mitochondrial-related gene expression and reduced expression of fibrosis-associated genes. These findings emphasize sex as a biological variable in Postn actions in heart and highlight distinct molecular mechanisms underlying male and female infarct healing.NEW & NOTEWORTHY We determined that cardiac wound healing following MI is periostin (Postn) dependent in male mice but Postn independent in female mice. To date, previous Postn knockout (KO) studies have exclusively used male animals. The current experimental design includes both sexes and reveals that the underlying mechanism of action to be sex dependent. Specifically, changes in the expression of collagen synthesis and cross-linking genes in the infarct scar are dependent on Postn expression in males only.

The extracellular matrix (ECM) is crucial in building the extracellular environment and translating extracellular information into biochemical signals that sustain tissue functions. Fibulin-5 (Fbln5) is a multifunctional ECM protein essential for forming elastic fibers and regulating cellular functions by binding to integrins. Although fibulin-5 expression decreases with age in human skin, its functional implications, particularly in epidermal stem cell regulation, remain largely unexplored. Here, we show that the loss of Fbln5 in mice leads to early impairments of epidermal stem cell properties that resemble changes observed during chronological skin aging. Fbln5 deficiency is associated with reduced expression of integrins and other cell junction proteins and decreased YAP activation in epidermal stem cells. Pharmacological inhibition of YAP reduces the fast-cycling stem cell region in mice and downregulates the fast-cycling epidermal stem cell marker SLC1A3 in human primary keratinocytes. At the cellular level, YAP activity and SLC1A3 expression are modulated by cell density, with low-density cultures exhibiting high nuclear YAP and elevated SLC1A3 expression, whereas high-density conditions suppress both. Under high-density conditions, fibulin-5 coating partially restores nuclear YAP localization and increases SLC1A3 expression. Together, these findings suggest that, beyond its structural role in elastic fiber formation, fibulin-5 contributes to the maintenance of epidermal stem cell balance during skin aging by linking extracellular alterations to YAP-dependent intracellular signaling.

Abstract Background/Aims Activated fibroblasts, called myofibroblasts, are responsible for the fibrosis seen in scleroderma. How to block myofibroblast activation and activity in scleroderma is unknown, but CCN3, a member of the CCN family of matricellular proteins, is anti-fibrotic and counteracts the profibrotic activity of the related protein CCN2. We have identified BLR-200 as a CCN3-derived peptide that retains CCN3’s antifibrotic properties in bleomycin-induced skin fibrosis. However, if CCN3’s and BLR-200’s antifibrotic properties translate to scleroderma patients is unknown. Methods To test the hypothesis that reduced CCN3 levels may exist in scleroderma patients, we used ELISAs to detect the amount of CCN2 and CCN3 in serum of healthy controls, early-onset diffuse (<24 months duration) scleroderma patients and those of later (>5 years) duration. To identify the fibroblast populations whose activation by bleomycin is suppressed by BLR-200, we conducted scRNAseq analysis of fibroblasts labelled postnatally with green fluorescent protein using mTmG mice, subjected or not to bleomycin-induced skin fibrosis in the presence or absence of BLR-200, that expressed a tamoxifen-dependent cre recombinase expressed under the control of a universal fibroblast-specific promoter/enhancer. Results CCN2 and CCN3 serum levels correlated well among healthy volunteers (controls) (r2=0.39, p < 0.03, N = 20), whereas scleroderma patients of < 2 years and of > 5 years duration showed patient-specific dysregulation of CCN2 and CCN3 protein levels (r2=0.048 and r2=0.116, respectively, N = 20). CCN2 and CCN3 levels increased in serum with patients of early duration (p < 0.05 vs p < 0.0001, respectively); however, increases in CCN3, but not CCN2, levels were observed in patients with late duration (p < 0.001 vs ns, respectively). In mice subjected to bleomycin-induced skin fibrosis, lineage tracing and scRNA-seq analyses revealed that myofibroblasts are derived from Pi16+/Col15+ve “universal” fibroblasts (N = 6, p < 0.01). BLR-200 prevented myofibroblast differentiation of Pi16+/Col15+ve “universal” fibroblasts in response to bleomycin toward an engrailed-1/Col8A1-positive subset of “universal” fibroblasts, a pro-fibrotic cell type previously shown to specifically upregulated in skin derived from scleroderma patients with active disease. Conclusion Given what is known about the relative activities of CCN2 and CCN3 in vivo, it is likely that serum levels of CCN3 rise in scleroderma patients in the body’s attempt to suppress CCN2-dependent fibrosis. Why this dysregulation appears to be patient-specific is unclear and requires further investigation. BLR-200 specifically targets the prevention of formation of an engrailed-1/Col8A1-positive fibroblast subpopulation that is specifically upregulated in skin in scleroderma patients. Therefore, BLR-200 appears to be a novel anti-fibrotic agent of potential translational relevance, particularly to patients with low serum levels of CCN3. Disclosure A. Leask: None. R.J. Stratton: None. B.A. Abdi: None. Z.J. Kannan: None. J. Nguyen: None. B.L. Riser: Corporate appointments; CEO, BLR Bio, LLC.

Abstract Background: The growth of primary malignant brain tumors (glioblastoma, GBM) leads to extensive changes in the composition and physical properties of the neural extracellular matrix (ECM). It is hypothesized that these changes modify the behavior of tumor-associated microglia and infiltrated macrophages (TAMs), which are the predominant immune cell population in GBM. Fibulin-3 is an ECM glycoprotein uniquely enriched in GBM, compared to the normal brain, that promotes tumor growth, vascularization and survival of the GBM stem cell (GSC) population. We have recently identified an autocrine effect of GSC-secreted fibulin-3 that dampens anti-tumor immune responses of TAMs against tumor cells. Here we describe a novel, complementary, immunosuppressive effect of this ECM protein by direct action on macrophages. Methods: The effects of fibulin-3 on macrophage cell viability, proliferation and migration, were tested with conventional assays using the myeloid cell lines Raw264.7, THP-1, and HMC3 (microglia). Human peripheral blood mononuclear cells and mouse bone marrow derived macrophages were isolated and treated with purified fibulin-3 to analyze signaling pathways and differential gene expression using cytokine arrays, phospho-RTK array, Western blotting and RNA sequencing. Tumor cells were co-cultured with fibulin-3 (or vehicle)-treated macrophages to assess their phagocytic activity. In vitro macrophage polarization was induced with cytokine cocktails to assess fibulin-3 effects. Genetic knockdown and pharmacological inhibition of the collagen receptor DDR2 were performed to test the requirement of this receptor for fibulin-3 effects in myeloid cells. Results: Fibulin-3 did not affect the proliferation of macrophage or microglia but increased the transmigration of these cells and decreased their phagocytic activity against tumor cells. These phenotypic changes induced by fibulin-3 were accompanied by increased expression of pro-migratory cytokines, upregulation of the phagocytosis inhibitor SIRP1α, and decreased expression of T cell co-stimulatory signals (CD137L, CD70). Fibulin-3 did not activate Notch/NF-kB signaling in macrophages as previously reported in glioma cells; instead, fibulin-3 increased the phosphorylation of the immunosuppressive receptor DDR2, as well as signaling mediated by Src/MAPK/RUNX2 activation. Fibulin-3 dampened the responses of cultured macrophages to an M[IFNg) -polarizing cytokine cocktail; this effect was partially dependent on DDR2 expression. Accordingly, the upregulation of SIRP1a by fibulin-3 was abolished by genetic or pharmacologic inhibition of DDR2. RNAseq data suggested a phenotypic change induced by fibulin-3 in macrophages corresponding to acquisition of ECM-remodeling, pro-angiogenic, and pro-fibrotic mechanisms. Conclusions: Our findings suggest that fibulin-3 secreted by tumor cells has direct immunosuppressive functions on the TAM population present in GBM, making this protein an attractive target to boost immune responses against the tumor. Citation Format: Soham Mitra, Somanath Kundu, Abigail Venskus, Mariano S. Viapiano. Direct immunosuppressive effect of the matricellular protein fibulin-3 on tumor-associated macrophages in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A006.

Excessive bone disruption, driven by upregulation of bone-degrading osteoclasts, occurs in several pathologies, including breast cancer osteolytic bone metastasis, a condition associated with poor prognosis and diminished quality of life for patients. The matricellular protein thrombospondin-1 (TSP-1) plays pleiotropic roles in physiological and pathological remodeling of several tissues, including bone, and in shaping the microenvironment of primary tumors and metastasis. This study aimed to explore the role of TSP-1 in bone remodeling associated with osteolytic bone metastasis. We have identified a C-terminal fragment of TSP-1, E123CaG, that inhibited RANKL-induced osteoclast differentiation. Cleavage of TSP-1 by serine proteases released by mature osteoclasts, particularly HTRA1, generated a similar fragment, indicating a possible role as a feedback mechanism of control. E123CaG bound RANK, the RANKL receptor on osteoclast precursors, and impaired early (the MAPKs p38 and JNK) and late (NFATc1) downstream signaling. E123CaG also bound osteoprotegerin (OPG), the decoy receptor of RANKL, in this case further potentiating its inhibitory activity by protecting it from degradation by proteases, including HTRA1. In an in vivo model of osteolytic bone metastasis, the expression of E123CaG by murine breast cancer cells reduced osteolytic lesions and prolonged survival, indicating that the C-terminal TSP-1 fragment is also active in vivo and can protect the bone against metastasis-associated osteolysis. Our findings indicate that the release in the bone environment of this TSP-1 fragment, with its unique dual ability to inhibit RANK signaling while potentiating OPG activity, represents an important mechanism to control bone remodeling in osteolytic bone metastasis.

Hypertension is a critical risk factor for vascular cognitive impairment; however, the precise molecular mechanisms underlying hypertension-induced neuronal injury remain poorly understood, hindering the development of effective neuroprotective strategies. Diminazene aceturate (DIZE), an activator of angiotensin-converting enzyme 2 (ACE2), has demonstrated neuroprotective effects in various neurological injury models, though its mechanisms in hypertensive brain damage are unknown. Here, we investigate the role of the matricellular protein CCN1 in hypertension-associated cognitive impairment and elucidate the potential neuroprotective mechanisms conferred by DIZE. A total of 80 genes were identified using RNA sequencing of HT22 hippocampal neurons treated with angiotensin II (AngII) alone or AngII plus DIZE, with CCN1 emerging as a hub linking mitochondrial dysfunction, autophagy, and oxidative stress pathways. Invitro, AngII-induced CCN1 upregulation, mitochondrial dysfunction, membrane-potential collapse, and excessive reactive oxygen species production were rescued by DIZE co-treatment. Mechanistically, CCN1 activated integrin αvβ6-TGF-β signaling to mediate neuronal injury, as these detrimental effects induced by AngII were abolished by genetic CCN1 knockdown or pharmacological blockade of integrin αvβ6 or TGF-β receptor 1, confirming a CCN1-αvβ6-TGF-β signaling axis. Actinomycin D transcription inhibition assays demonstrated that DIZE suppressed CCN1 at the post-transcriptional level, specifically by accelerating CCN1 mRNA degradation and reducing its half-life, thereby restoring mitochondrial integrity. Building on these mechanistic insights, chronic hypertension was induced in mice by continuous subcutaneous AngII infusion. AngII-induced spatial-memory and object-recognition deficits in Barnes maze, novel object recognition, and Y-maze tests were largely reversed by DIZE treatment, demonstrating that restoration of mitochondrial function through CCN1 destabilization ameliorates hypertension-related cognitive impairment. We identify a novel CCN1-integrin αvβ6-TGF-β-mitochondrial dysfunction signaling axis as a key mediator of hypertension-induced cognitive impairment and demonstrate that DIZE confers neuroprotective effects through post-transcriptional suppression of CCN1 via accelerated mRNA degradation. These findings advance our mechanistic understanding of hypertensive brain injury and establish a rational foundation for the clinical development of CCN1-targeted therapeutic interventions.

In Osteogenesis Imperfecta (OI), phenotypic variability and the limited predictive value of genotype-phenotype correlations underscore the need for reliable predictive marker of disease severity. Periostin is a matricellular protein involved in bone formation, remodeling, and response to mechanical stress. It interacts with type I collagen and modulates osteoblast activity via Wnt/β-catenin and TGF-β signaling. Given its established role in other bone disorders, we hypothesized that circulating periostin may be a relevant biomarker in OI. We performed a matched case-control analysis of serum periostin levels in 61 adult patients with OI and 61 age-, sex-, and BMI-matched controls. Periostin was measured by ELISA. Associations between periostin levels and clinical variables were assessed using t-tests, Pearson correlations, and multivariable linear regression models. Mean periostin levels were significantly higher in OI patients than in controls (796.5 ± 209 vs. 713.6 ± 167 pmol/L, p = 0.017). Among OI patients, higher periostin level was associated with female sex (p = 0.01), presence of scoliosis (p = 0.01), and Sillence type III (p = 0.05). Positive correlations were observed between periostin and markers of axial skeletal severity as height-wingspan discrepancy (r = 0.30, p = 0.023). In multivariable analysis, the number of severe fractures (defined as femur/pelvis/humerus/vertebral fractures) was independently associated with higher periostin level (β = 25.6, p = 0.041), while smoking was negatively associated (β = -269.8, p = 0.012). This study is the first to report the elevated circulating level of periostin in adults with OI and its association with disease severity.

The bone extracellular matrix (ECM) is no longer viewed as a passive scaffold, but as an instructive niche that actively governs skeletal development, homeostasis, and regeneration. It functions beyond mechanical and structural support, serving as a solid-phase signaling hub that sequesters and releases morphogens such as TGF-β, BMPs, and Wnt ligands, thereby coupling matrix remodeling to mesenchymal stromal cell differentiation, osteogenic progenitor expansion, and late-stage mineralization. In this review, we summarize the current understanding of how collagens, glycoproteins, and proteoglycans assemble into a dynamic, viscoelastic composite with multiscale porosity and pronounced stiffness gradients that shape skeletal tissue. We discuss how these physical and biochemical properties are continuously shaped by ECM-modifying enzymes, including lysyl oxidases (LOX/LOXLs), transglutaminases, MMPs, and ADAMTS proteases, and how the ECM is further regulated by non-enzymatic glycation in aging and diabetes. We also examine the role of osteocytes as orchestrators of ECM turnover, emphasizing perilacunar and canalicular remodeling and the PHEX/MEPE/ASARM axis in coordinating mineralization and phosphate homeostasis. In the context of regeneration, we summarize emerging roles for matricellular proteins such as periostin and tenascin-C in coordinating regenerative programs. The bone ECM is a dynamically regulated structure whose biochemical and physical properties are continuously modified by enzymatic and non-enzymatic processes. Osteocytes play a central role in orchestrating ECM turnover and mineralization. Matricellular proteins, particularly osteolectin (OLN), exemplify how matrix-associated ligands can activate Wnt signaling through integrin α₁β₁. We argue that systematic mining of the bone ECM-secreted proteome will uncover additional cell-type-restricted anabolic cues and therapeutic opportunities for genetic dysplasias, fracture non-unions, osteoporosis, and metabolic bone fragility.

An early event after lung injury is extracellular matrix (ECM) remodeling and the formation of a provisional matrix. While megakaryocytes and platelets (Mgk/plt) play important roles in hemostasis, their impact on the matrix in lung injury is not fully understood. Using lung intravital microscopy, 3D large area scanning with multiphoton confocal hybrid imaging, and label-free quantitative proteomics, the matricellular protein thrombospondin-1 (TSP1) arising from Mgk/plt protects the lung from alveolar injury. Mgk/plt cell-specific Thbs1 knockout (cKO) mice show increased alveolar barrier disruption with exaggerated neutrophil-mediated injury. The cKO mice exhibit striking extracellular matrix re-organization with reduction in basement membrane matrixprotein COL6A1 after injury. Moreover, cKO mice increase Mgk numbers to regions of fibrillar collagen deposition and alveolar leak. Our findings indicate Mgk/plt-derived TSP1 represents a key mechanism of matrix stabilization by protecting the basement membrane from neutrophil-mediated proteolytic damage, regulating injury severity and Mgk numbers at the alveolar interface.

Female breast development occurs at puberty and undergoes many cyclic changes under normal physiological conditions, like pregnancy, lactation and involution. The breast epithelium is surrounded by a heterogenous stroma that encompasses various cell types, including fibroblasts, immune cells, adipocytes, endothelial cells and an extracellular matrix (ECM). The ECM is a complex molecular meshwork composed of a variety of matricellular proteins and ECM remodelling enzymes, including proteases. Dynamic remodelling of the ECM is fundamental to the organisation and function of the mammary gland and is associated with stemness. It is often aberrantly regulated in breast cancer, which still has the highest incidence and mortality rates in women worldwide. Improved models could contribute to a better understanding of cell-matrix interactions, including in the stem cell niche, and ECM remodelling in health and tumorigenesis. This could lay the groundwork for therapeutic strategies that also target the breast cancer ECM for improved precision medicine tools.