AGEs induce ectopic endochondral ossification in intervertebral discs

Illien-Jünger, Svenja; Torre, Olivia M.; Kindschuh, William F.; Chen, X; Laudier, Damien M.; Iatridis, James C.

doi:10.22203/ecm.v032a17

Cited by 35 publications

(29 citation statements)

References 71 publications

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“…It has been shown that ectopic calcifications in IVDs are a known characteristic of IVD degeneration (Hristova et al, ; Illien‐Jünger et al, ). The observed small round cells, resembling chondrocyte morphology, in the Tnmd − / − NP prompted us to test whether the loss of Tnmd is accelerating hypertrophic chondrocyte‐like occurrence.…”

Section: Resultsmentioning

confidence: 99%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin (Tnmd) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of Tnmd. Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. Tnmd knockout (Tnmd−/−) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, Tnmd and chondromodulin I (Chm1, the only homologous gene to Tnmd) double knockout (Tnmd−/−Chm1−/−) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of Tnmd in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration.

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Section: Resultsmentioning

confidence: 99%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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“…Regarding TRPS1, which is involved in chondrogenesis and cartilage biology [ 15 ], we hypothesized that increase in its expression after miR-221 depletion may contribute to avoid undesired ossification in IVD microenvironment slowing down the degeneration process. In fact, calcification of cartilage cells is one of many events associated with IDD multifactorial disease, together with apoptosis, senescence, inflammation, and alterations in the ECM [ 2 , 47 ]. Therefore, since TRPS1 acts as a repressor of the function of RUNX2 [ 15 , 48 ], the master regulator of osteogenesis [ 20 ], the increased TRPS1 expression may contribute to maintain RUNX2 basal level and repress the RUNX2-mediated transactivation of genes associated with cartilage hypertrophy and ECM degradation, such as collagen type X alpha 1 chain (COL10A1), alkaline phosphatase (ALP), and MMPs [ 49 ], also in the IVD tissue.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-221 silencing attenuates the degenerated phenotype of intervertebral disc cells

Penolazzi

Lambertini

Bergamin

et al. 2018

Aging

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The aim of this study was to investigate the role of an antichondrogenic factor, MIR221 (miR-221), in intervertebral disc degeneration (IDD), and provide basic information for the development of a therapeutic strategy for the disc repair based on specific nucleic acid based drugs, such as miR-221 silencing. We established a relatively quick protocol to minimize artifacts from extended in vitro culture, without selecting the different types of cells from intervertebral disc (IVD) or completely disrupting extracellular matrix (ECM), but by using the whole cell population with a part of resident ECM. During the de-differentiation process miR-221 expression significantly increased. We demonstrated the effectiveness of miR-221 silencing in driving the cells towards chondrogenic lineage. AntagomiR-221 treated cells showed in fact a significant increase of expression of typical chondrogenic markers including COL2A1, ACAN and SOX9, whose loss is associated with IDD. Moreover, antagomiR-221 treatment restored FOXO3 expression and increased TRPS1 expression levels attenuating the severity grade of degeneration, and demonstrating in a context of tissue degeneration and inflammation not investigated before, that FOXO3 is target of miR-221. Data of present study are promising in the definition of new molecules useful as potential intradiscal injectable biological agents.

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“…However, AGEs can also induce enzymatic activity and matrix catabolism, for example by binding to the receptor for AGEs (RAGE) (Ott et al, 2014). Some have suggested an important role for the AGE/RAGE pathway in diabetes and AGE induced IVD degeneration (Fields et al, 2015, Illien-Junger et al, 2016 however future studies will investigate the role of this interaction further especially as it pertains to dietary AGEs. Together with the literature, our assessment of SHG intensity and CHP binding suggests that dietary AGEs lead to increased glycation within the AF collagen matrix, inducing collagen fibrillar disorder and molecular damage.…”

Section: Discussionmentioning

confidence: 99%

Dietary Advanced Glycation End-Product Consumption Leads to Mechanical Stiffening of Murine Intervertebral Discs

Krishnamoorthy

Hoy

Natelson

et al. 2018

Preprint

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StatementDietary advanced glycation end-products (AGE) lead to sex-specific intervertebral disc structural and functional changes and may be targeted for promoting spinal health especially in diabetes where AGEs form rapidly. ABSTRACTBack pain is a leading cause of disability strongly associated with intervertebral disc (IVD) degeneration. Reducing structural disruption and catabolism in IVD degeneration remains an important clinical challenge. Pro-oxidant and structuremodifying advanced glycation end-products (AGEs) contribute to obesity and diabetes, which are associated with increased back pain, and accumulate in tissues due to hyperglycemia or ingestion of foods processed at high heat.Collagen-rich IVDs are particularly susceptible to AGE accumulation due to their slow metabolic rates yet it is unclear if dietary AGEs can cross the endplates to accumulate in IVDs. We apply a dietary mouse model to test the hypothesis that chronic consumption of high AGE diets results in sex-specific IVD structural disruption and functional changes. High AGE diet resulted in AGE accumulation in IVDs and increased IVD compressive stiffness, torque range, and failure torque, particularly for females. These biomechanical changes were likely caused by significantly increased AGE crosslinking in the annulus fibrosus, measured by multiphoton imaging. Increased collagen damage measured with collagen hybridizing peptide may be a risk factor for IVD degeneration as these animals age. The greater influence of high AGE diet on females is an important area of future investigation that may involve AGE receptors, known to interact with estrogen. We conclude high AGE diets can be a source for IVD crosslinking and collagen damage known to be important in IVD degeneration. This suggests dietary and other interventions that modify AGEs warrant further investigation and may be particularly important for diabetics where AGEs accumulate more rapidly.

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AGEs induce ectopic endochondral ossification in intervertebral discs

Cited by 35 publications

References 71 publications

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

MicroRNA-221 silencing attenuates the degenerated phenotype of intervertebral disc cells

Dietary Advanced Glycation End-Product Consumption Leads to Mechanical Stiffening of Murine Intervertebral Discs

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