Biology subjects

Bou-Gharios, G.

Publications and source records attributed to Bou-Gharios, G..

14 recordsLinked to original sources

bioRxiv2026

Unraveling the metabolic landscape of alkaptonuria through a human-relevant in vitro liver disease model

Alkaptonuria (AKU) is a rare inherited metabolic disorder of tyrosine catabolism caused by a deficient homogentisate 1,2-dioxygenase (HGD) enzyme. This results in the accumulation of homogentisic acid (HGA), driving a progressive multisystem pathology characterized by debilitating early-onset osteoarthritis due to connective tissue degeneration. While previous in vitro studies have primarily relied on exogenous HGA exposure in osteoarticular cell models, the direct metabolic consequences of endogenous HGD deficiency within its native hepatic context remain poorly understood. Here, we established the first human-relevant HGD knockout hepatic in vitro model using a universal in-house-developed homology-directed repair approach. Integrative multi-omic analysis revealed that HGD deficiency induces widespread metabolic rewiring extending beyond disrupted tyrosine catabolism. HGD-deficient hepatocytes exhibited elevated oxidative stress accompanied by impaired mitochondrial respiration and a pseudohypoxic metabolic adaptation toward increased glycolytic dependency. Despite this glycolytic shift, the cells displayed reduced anabolic and translational activity alongside attenuated proliferation, consistent with a chronic stress-adaptive survival state rather than a proliferative metabolic phenotype. This study provides systems-level insights into the pathophysiology of AKU and establishes a versatile platform for mechanistic and therapeutic investigation.

cell biology↗

bioRxiv2026

Loss of CD109 Amplifies NF-κB Signaling and Inflammatory Reprogramming in Dermal Fibroblasts

Fibroproliferative diseases such as systemic sclerosis are complex conditions characterized by chronic skin inflammation and progressive fibrosis, with fibroblast activation as a central feature. While Transforming Growth Factor Beta (TGF-{beta}) signaling is a well-established driver of fibrosis in SSc, inflammatory pathways such as Nuclear Factor Kappa B (NF-{kappa}B) also contribute substantially to disease morbidity. We previously identified CD109 as a TGF-{beta} co-receptor and negative regulator of fibrotic signaling; however, its role in inflammatory signaling remains unknown. Here, we investigate the function of CD109 in regulating inflammatory signaling in skin fibroblasts. We show that, CD109 co-localizes and associates with Toll-like receptors (TLR2, TLR4) and tumor necrosis factor receptors (TNFRI, TNFRII), and that loss of CD109 enhances TNF--induced NF-{kappa}B activation and reprograms cytokine production in human dermal fibroblasts. Furthermore, both global and fibroblast-specific CD109 knockout mice exhibit increased immune cell infiltration and skin inflammation. In parallel, single-cell transcriptomic analyses across a pan-disease fibroblast atlas show that CD109 expression is preferentially maintained in structural and homeostatic fibroblast subtypes, whereas immune-interacting fibroblast subsets consistently display decreased CD109 levels. Pathway-level analyses of fibroblast pseudobulk samples reveal altered activity of canonical inflammatory pathways in SSc compared to healthy skin. Together, these findings identify CD109 as a fibroblast-intrinsic negative regulator of inflammatory signaling and suggest a broader role for CD109 in modulating inflammatory responses in systemic sclerosis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/736423v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@ba5107org.highwire.dtl.DTLVardef@1de28aorg.highwire.dtl.DTLVardef@3e8a6org.highwire.dtl.DTLVardef@9f1a82_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: CD109 Restrains Fibroblast-Driven Inflammation by Modulating NF-{kappa}B Signaling. Generated using FigureLabs.ai and edited using Adobe Photoshop. C_FIG

cell biology↗

bioRxiv2026

Liver-directed AAV gene therapy metabolically corrects AKU in Hgd deficient mice

BackgroundAlkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by deficiency of homogentisate 1,2-dioxygenase (HGD), resulting in systemic accumulation of homogentisic acid (HGA), ochronosis, and progressive multisystem disease. Although nitisinone (NTBC) lowers HGA levels, it does not correct the underlying genetic defect and induces hypertyrosinemia, highlighting the need for curative treatment approaches. We evaluated liver-directed adeno-associated virus (AAV)-mediated HGD gene therapy as a potential treatment for AKU. MethodsHgd-deficient (Hgd-/-) mice received liver-directed AAV2/8 vectors expressing codon-optimized human HGD under a liver-specific promoter. Reporter vectors were first used to assess hepatic biodistribution and transduction efficiency. Therapeutic efficacy was subsequently evaluated following AAV2/8-HGD administration (1 x 1012 vg/mouse). HGD expression was assessed by DNAscope, Western blotting, and RT-qPCR. Metabolic correction was determined using targeted LC-MS/MS and untargeted LC-HRMS metabolomics and compared with NTBC-treated Hgd-/- mice. ResultsReporter studies demonstrated liver-predominant transduction, with dose-dependent hepatocyte transduction reaching 89-93% at the highest dose. AAV2/8-HGD treatment produced robust hepatic HGD expression, with codon-optimized human HGD transcript levels approximately 33-fold higher than endogenous murine Hgd expression. Twelve weeks after treatment, plasma and urinary HGA levels were significantly reduced, with plasma HGA restored to near wild-type concentrations. Untargeted metabolomics further demonstrated marked reductions in HGA-derived phase I and II metabolites and revealed significant modulation of tricarboxylic acid cycle metabolism, consistent with partial restoration of metabolic homeostasis. Compared with NTBC-treated mice, AAV2/8-HGD achieved comparable plasma HGA reduction without elevation of upstream tyrosine pathway metabolites. ConclusionsLiver-directed AAV2/8-HGD gene therapy achieved substantial biochemical correction in Hgd-/- mice and restored metabolic flux without inducing hypertyrosinemia. These findings provide proof-of-concept supporting AAV-mediated HGD replacement as a promising long-term therapeutic strategy for AKU.

genetics↗

bioRxiv2024

Sex specific knee joint soft tissue mineralization with Fibrillin-1 mutation in male Tight Skin mice.

Articular soft tissue mineralization and ossification are clear pathological signs of osteoarthritis joints. However their molecular and cellular aetiologies remain largely unknown. TGF-{beta} family members are known contributors to both pathological ossification and osteoarthritis development. In this study, we used a Fibrillin-1 mutant mouse, the Tight Skin mouse (TSK), to define the detrimental effects of abnormal Fbn1 in TSK mice and known high TGF-{beta} activity in joint pathology such as articular soft tissue mineralization and ossification. Knee joints of male and Female TSK and Wild-type (WT) littermates were analysed my micro-CT imaging and histology for articular soft tissue pathologies, as well as OA severity. Both aged (10, 26, 35 and 52wks) and following in vivo non-invasive repetitive joint overloading were used. We find that male TSK mice develop spontaneous soft tissue ossification from 26wks of age, followed by increased osteoarthritis at 1 year-old. In addition, knee joint overloading induced ligament and meniscal mineralisation and ossification in both WT and TSK male mice, but were significantly more severe in TSK knees, including ossification of the patella ligament and synovial lining. In contrast, female TSK knees did not develop more severe soft tissue mineralisation compared to littermate WT mice in neither aged nor overloaded knees. We conclude that Fbn1 mutation, and possibly overactive TGF-{beta} activity in TSK mice, induce articular soft tissue ossification and osteoarthritis in a sex-specific manner. Further studies are needed to confirm the specific signalling involved and the relative protection from female mice from such pathologies.

pathology↗

bioRxiv2023

Bile is a route of excretion for homogentisic acid in alkaptonuria

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of the metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type-1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in the bile in AKU (mean [{+/-}SD] = 1003[{+/-}410] mol/L; nitisinone-treated AKU mean [{+/-}SD] = 45[{+/-}23] mol/L). Biliary tyrosine, HPPA and HPLA are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion and possible metabolism of HGA by the gut microbiome. These data provide new insights into the pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. Take-home messageThis paper presents the first observation of elevated hepatobiliary circulation of metabolites associated with disease in alkaptonuria, including homogentisic acid in addition to tyrosine and the tyrosine metabolites 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid on nitisinone treatment.

biochemistry↗

bioRxiv2023

Skeletal progenitor LRP1-mediated endocytosis is critical for synovial joint formation and bone growth

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E13.5 and onwards, especially in the perichondrium, the stem cell layer surrounding developing limbs essential for bone formation. Lrp1 deficiency in these stem cells causes joint fusion, malformation of cartilage/bone template and markedly delayed or lack of primary ossification along with aberrant accumulation of some of the LRP1 ligands at as early as E16.5. These early abnormalities result in multiple and persistent skeletal defects including a severe deficit in hip joint and patella, and markedly deformed and low-density long bones leading to dwarfism and impaired mobility. Mechanistically, we show that LRP1 regulates core non-canonical WNT/planar cell polarity (PCP) components that may explain the malformation of long bones. LRP1 directly binds to Wnt5a, facilitates its cell-association and endocytic recycling. Using Xenopus as a model system we show that loss or gain of LRP1 function leads to shortened tadpoles similar to Wnt5a and Wnt11 overexpression, indicating a role for LRP1 in WNT/PCP signalling. Finally, we show the colocalisation LRP1 and Wnt5a in the developing mouse limbs and that Lrp1 deficiency diminishes graded distribution of Wnt5a and Vangl2. We propose that skeletal progenitor LRP1 plays a critical role in formation and maturity of multiple bones and joints by regulating morphogen signalling, providing novel insights into the fundamental processes of morphogenesis and the emergence of skeletal pathologies.

developmental biology↗

bioRxiv2022

Uncovering the ligandome of low-density lipoprotein receptor-related protein 1 in cartilage: a top-down approach to identify therapeutic targets

The low-density lipoprotein receptor-related protein 1 (LRP1) is a cell-surface receptor ubiquitously expressed in adult tissues. It plays tissue-specific physiological roles by mediating endocytosis of a diverse range of extracellular molecules. Dysregulation of LRP1 is involved in multiple conditions including Alzheimers disease, atherosclerosis and osteoarthritis (OA). However, little information is available about the specific ligand profile (ligandome) for each tissue, which would lead to better understanding of its role in disease states. Here, we investigated adult articular cartilage where impaired LRP1-mediated endocytosis leads to tissue destruction. We used a top-down approach involving analysis of human chondrocyte secretome, direct binding assays and validation in LRP1-deficient fibroblasts, as well as a novel Lrp1 conditional knockout (KO) mouse model. We found that inhibition of LRP1-mediated endocytosis results in cell death, alteration of the entire secretome and transcriptional modulations in human chondrocytes. We have identified more than 50 novel ligand candidates and confirmed direct LRP1 binding of HGFAC, HMGB1, HMGB2, CEMIP, SLIT2, ADAMTS1, IGFBP7, SPARC and LIF. Our in vitro endocytosis assay revealed the correlation of their affinity for LRP1 and the rate of endocytosis. Moreover, a conditional LRP1 KO mouse model demonstrated a critical role of LRP1 in regulating the high-affinity ligands in cartilage in vivo. This systematic approach revealed the extent of the chondrocyte LRP1 ligandome and identified potential novel therapeutic targets for OA.

cell biology↗

bioRxiv2021

The anterior cruciate ligament in murine post-traumatic osteoarthritis: markers and mechanics

1Osteoarthritis (OA) is a whole joint disease that affects all knee joint tissues. Ligaments, a matrix-rich connective tissue, play an important mechanical function that stabilises the knee joint and yet their role in OA is not well studied. Recent studies have shown that ligament extracellular matrix (ECM) structure is compromised in the early stages of OA, but it remains unclear how this affects ligament function and biomechanics. In this study, the aim was to investigate the structural, cellular and viscoelastic changes in the anterior cruciate ligament (ACL) in a murine non-invasive post-traumatic OA (PTOA) model. Non-invasive mechanical loading of the knee joint of C57BL/6J mice (10-week-old) was used as a PTOA model. Knee joints were analysed for joint space mineralisation and the ACLs were assessed with histology and mechanical testing. PTOA knee joints had a 33-46% increase in joint space mineralisation and PTOA knee joint ACLs exhibited ECM modifications, including collagen birefringence and COL2 and proteoglycan deposition. ECM changes were associated with cells expressing chondrogenic markers (SOX9 and RUNX2) expanding from the tibial enthesis to the ACL midbody. Viscoelastic and mechanical changes in the ACLs from PTOA knee joints included a 20-21% decrease in tangent modulus at 2MPa of stress, and a decrease strain rate sensitivity at higher strain rates and a significant increase in relaxation during stress-relaxation, but no changes to hysteresis and ultimate load to failure. These results demonstrate that ACL pathology and viscoelastic function is compromised in murine PTOA knee joints and provides further evidence of the important role of ligaments in the knee joint organ in health and disease.

pathology↗

bioRxiv2020

Laminin N-terminus α31 expression during development in an inducible-transgenic mouse model is lethal and causes a multitude of tissue-specific defects

Laminins are essential components of all basement membranes where they regulate an extensive array of tissue functions. Alternative splicing from the laminin 3 gene produces a non-laminin but netrin-like protein, Laminin N terminus 31 (LaNt 31). LaNt 31 is widely expressed in intact tissue and is upregulated in epithelial cancers and during wound healing. In vitro functional studies have shown that LaNt 31 can influence numerous aspects of epithelial cell behaviour via modifying matrix organisation, suggesting a new model of laminin auto-regulation. However, the function of this protein has not been established beyond the epithelium and it has never been studied in vivo. Here, a mouse transgenic line was generated using the ubiquitin C promoter to drive inducible expression of LaNt 31. When expression was induced at embryonic day 15.5, LaNt 31 transgenic animals were not viable at birth, exhibiting localised regions of erythema. Numerous striking defects were apparent histologically, including extra-vascular erythrocytes in multiple tissues, kidney epithelial detachment, tubular dilation, interstitial bleeding, and thickening of tubule basement membranes, disruption of the epidermal basal cell layer and of the hair follicle outer root sheath, and ~50% reduction of cell numbers in the liver associated with depletion of hematopoietic erythrocytic foci. These findings demonstrate that LaNt 31 can influence tissue morphogenesis during development. More broadly, these data provide the first in vivo evidence to support an emerging model of laminin self-regulation and provide a valuable model for onward investigation into this important area. Summary StatementExpression during development of Laminin N-terminus 31, a netrin-like laminin splice isoform, caused defects indicating basement membrane disruption in multiple tissues; providing the first in vivo evidence for laminin self-regulation.

cell biology↗

bioRxiv2020

Collagen (I) homotrimer does not cause bone fragility but potentiates the osteogenesis imperfecta (oim) mutant allele

Type I collagen is the major structural component of bone where it exists as an (1)2(2)1 heterotrimer in all vertebrates. The osteogenesis imperfecta (oim) mouse model comprising solely homotrimeric (1)3 type I collagen, due to a dysfunctional 2 chain, has a brittle bone phenotype implying that the heterotrimeric form is required for physiological bone function. However, humans with rare null alleles preventing synthesis of the 2 chain have connective tissue and cardiovascular abnormalities (cardiac valvular Ehlers Danlos Syndrome), without evident bone fragility. Conversely a prevalent human single nucleotide polymorphism leading to increased homotrimer synthesis is associated with osteoporosis. Whilst the oim line is well-studied, whether homotrimeric type I collagen is functionally equivalent to the heterotrimeric form in bone has not been demonstrated. Col1a2 null and oim mouse lines were used in this study and bones analysed by microCT and 3-point bending. RNA was also extracted from heterozygote tissues and allelic discrimination analyses performed using qRT-PCR. Here we comprehensively show for the first time that mice lacking the 2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However Mendelian inheritance was affected in male mice of both lines and male mice null for the 2 chain exhibited age-related loss of condition. The brittle bone phenotype of oim homozygotes could result from detrimental effects of the oim mutant allele, however, the phenotype of oim heterozygotes is known to be less severe. We used allelic discrimination to show that the oim mutant allele is not downregulated in heterozygotes. We then tested whether gene dosage was responsible for the less severe phenotype of oim heterozygotes by generating compound heterozygotes. Data showed that compound heterozygotes had impaired bone structural properties as compared to oim heterozygotes, albeit to a lesser extent than oim homozygotes. Hence, we concluded that the presence of heterotrimeric collagen-1 in oim heterozygotes alleviates the effect of the oim mutant allele but a genetic interaction between homotrimeric collagen-1 and the oim mutant allele leads to bone fragility.

physiology↗

bioRxiv2020

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

Background and Purposealkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of the enzyme homogentisate 1,2-dioxygenase (HGD). The primary biochemical consequence of HGD-deficiency is increased circulating homogentisic acid (HGA), which is central to AKU disease pathology. The aim of this study was to investigate the wider metabolic consequences of targeted Hgd disruption. Experimental Approachthe first metabolomic analysis of the Hgd-/- AKU mouse model was performed. Urinary metabolites altered in Hgd-/- were further validated by showing that the HGA-lowering drug nitisinone reversed their direction of alteration in AKU Key Resultscomparison of Hgd-/- (AKU) versus Hgd+/- (heterozygous control) urine revealed increases in HGA and a group of 8 previously unreported HGA-derived transformation products from phase I and II metabolism. HGA biotransformation products HGA-sulfate, HGA-glucuronide, HGA-hydrate and hydroxymethyl-HGA were also decreased in urine from both mice and patients with AKU on the HGA-lowering agent nitisinone. Hgd knockout also revealed a host of previously unrecognised associations between tyrosine, purine and TCA cycle metabolic pathways. Conclusion and ImplicationsAKU is rare, but our findings further what is currently understood about tyrosine metabolism more generally, and show for the first time that phase I and II detoxification is recruited to prevent accumulation of endogenously-produced metabolites in inborn errors of metabolism. The data highlight the misconception that phase I and II metabolic biotransformations are reserved solely for drug clearance; these are ancient mechanisms, which represent new potential treatment targets in inherited metabolic diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/044347v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@12b0b2forg.highwire.dtl.DTLVardef@eb4bacorg.highwire.dtl.DTLVardef@1b511e1org.highwire.dtl.DTLVardef@a8ef8e_HPS_FORMAT_FIGEXP M_FIG C_FIG Bullet point summaryWhat is already known O_LIIncreased circulating homogentisic acid is central to disease pathology in the inherited metabolic disease alkaptonuria C_LIO_LIThe Hgd knockout mouse, created in our laboratory, accurately models human alkaptonuria C_LI What this study adds O_LIPhase I and II biotransformations are recruited in alkaptonuria for detoxification of homogentisic acid C_LIO_LIThese data challenge misconceptions that phase I and II metabolism is solely for drug clearance C_LI Clinical significance O_LIPhase I and II metabolic processes represent new treatment targets in inherited metabolic diseases C_LIO_LIThe molecular pathology of AKU extends much further than the known alteration to tyrosine metabolism C_LI

biochemistry↗

bioRxiv2020

Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of CCN2.

CCN2 is a matricellular protein involved in several critical biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. CCN2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development, however its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). CCN2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-CT, and processed for histology. Sections were stained with toluidine blue and scored using the OARSI grading system. In the non-invasive model cartilage lesions were present in the lateral femur but no significant differences were observed between wildtype (WT) and CCN2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments but no significant differences were observed between WT and CCN2 KO mice at 2, 4, and 8 weeks post-surgery. We conclude that CCN2 deletion in chondrocytes did not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a critical player in protecting cartilage from the degeneration associated with PTOA. Summary StatementPost-natal deletion of CCN2 in chondrocytes does not affect the development of post-traumatic osteoarthritis in mice.

pathology↗

bioRxiv2019

Syndecan-3 enhances anabolic bone formation through WNT signalling

Osteoporosis is the most common age-related metabolic bone disorder, which is characterised by low bone mass and deterioration in bone architecture, with a propensity to fragility fractures. The best treatment for osteoporosis relies on stimulation of osteoblasts to form new bone and restore bone structure, however anabolic therapeutics are few and their use is time-restricted. Here we report that Syndecan-3 (SDC3) increases new bone formation through enhancement of WNT signalling. Young adult Sdc3-/- mice have a low bone volume phenotype associated with reduced bone formation, increased bone marrow adipose tissue (BMAT), increased bone fragility and a blunted anabolic bone formation response to mechanical loading. The premature osteoporosis-like phenotype of Sdc3-/- mice is primarily explained by delayed osteoblast maturation and impaired osteoblast function, with contributing increased osteoclast-mediated bone resorption. Mechanistically, SDC3 enhances canonical WNT signalling in osteoblasts through stabilisation of Frizzled 1, making SDC3 an attractive target for novel anabolic drug development.

cell biology↗

bioRxiv2019

Meniscal and ligament modifications in spontaneous and post-traumatic mouse models of osteoarthritis

Osteoarthritis (OA) is a whole joint disease that affects all joint tissues, with changes in the articular cartilage (AC), subchondral bone and synovium. Pathologies in menisci and ligaments, however, are rarely analysed, although both are known to play vital roles in the mechanical stability of the joint. The aim of our study was to describe the pathological changes in menisci and ligament during disease development in murine spontaneous and post-traumatic surgically-induced OA and to quantify tissue mineralisation in the joint space using {micro}CT imaging during OA progression. Knees of Str/ort mice (spontaneous OA model; 26-40wks) and C57CBA F1 mice following destabilisation of medial meniscus (DMM) surgery (post-traumatic OA model; 8wks after DMM), were used to assess histological meniscal and ligament pathologies. Joint space mineralised tissue volume was quantified by {micro}CT. Meniscal pathological changes in Str/ort mouse knees were associated with articular cartilage lesion severity. These meniscal changes included ossification, hyperplasia, cell hypertrophy, collagen type II deposition and SOX9 expression in the fibrous region near the attachment to the knee joint capsule. Anterior cruciate ligaments exhibited extracellular matrix changes and chondrogenesis particularly at the tibial attachment site, and ossification was seen in collateral ligaments. Similar changes were confirmed in the post-traumatic DMM model. {micro}CT analysis showed increased joint space mineralised tissue volume with OA progression in both the post-traumatic and spontaneous OA models. Modifications in meniscal and ligament mineralisation and chondrogenesis are seen with overt AC degeneration in murine OA. Although the aetiology and the consequences of such changes remain unknown, they will influence stability and load transmission of the joint and may therefore contribute to OA progression. In addition, these changes may have important roles in movement restriction and pain, which represent major human clinical symptoms of OA. Description of such soft tissue changes, in addition to AC degradation, should be an important aspect of future studies in mouse models in order to furnish a more complete understanding of OA pathogenesis. Summary statementThis manuscript describes histological changes in mouse knee joints in two models of osteoarthritis and correlates joint space mineralised tissue volume measured by {micro}CT with disease severity.

pathology↗