scholarly journals Tenomodulin and Chondromodulin-1 Are Both Required to Maintain Biomechanical Function and Prevent Intervertebral Disc Degeneration

Cartilage ◽  
2021 ◽  
pp. 194760352110296
Author(s):  
Theodor Di Pauli von Treuheim ◽  
Olivia M. Torre ◽  
Emily D. Ferreri ◽  
Philip Nasser ◽  
Angelica Abbondandolo ◽  
...  
Keyword(s):  
Fluid Flow ◽  
Intervertebral Disc ◽  
Lumbar Vertebrae ◽  
Biomechanical Properties ◽  
Double Knockout ◽  
Single Mutant ◽  
C Terminus ◽  
Organ Level ◽  
Underlying Mechanisms ◽  
Ivd Degeneration

Objective The underlying mechanisms and molecular factors influencing intervertebral disc (IVD) homeostasis and degeneration remain clinically relevant. Tenomodulin (Tnmd) and chondromodulin (Chm1) are antiangiogenic transmembrane glycoproteins, with cleavable C-terminus, expressed by IVD cells that are implicated in the onset of degenerative processes. We evaluate the organ-level biomechanical impact of knocking out Tnmd alone, and Tnmd and Chm1, simultaneously. Design Caudal (c5-8) and lumbar vertebrae (L1-4) of skeletally mature male and female 9-month-old wildtype (WT), Tnmd knockout (Tnmd−/−), and Tnmd/Chm1 double knockout (Tnmd−/−/Chm−/−) mice were used ( n = 9-13 per group). Disc height index (DHI), histomorphological changes, and axial, torsional, creep, and failure biomechanical properties were evaluated. Differences were assessed by one-way ANOVA with post hoc Bonferroni-corrected comparisons ( P < 0.05). Results Tnmd−/−/Chm1−/− IVDs displayed increased DHI and histomorphological scores that indicated increased IVD degeneration compared to the WT and Tnmd−/− groups. Double knockout IVDs required significantly less torque and energy to initiate torsional failure. Creep parameters were comparable between all groups, except for the slow time constant, which indicated faster outward fluid flow. Tnmd−/− IVDs lost fluid faster than the WT group, and this effect was amplified in the double knockout IVDs. Conclusion Knocking out Tnmd and Chm1 affects IVD fluid flow and organ-level biomechanical function and therefore may play a role in contributing to IVD degeneration. Larger effects of the Tnmd and Chm1 double knockout mice compared to the Tnmd single mutant suggest that Chm1 may play a compensatory role in the Tnmd single mutant IVDs.

scholarly journals LRP5-deficiency in OsxCreERT2 mice models intervertebral disc degeneration by aging and compression

2019 ◽  
Author(s):  
Matthew J. Silva ◽  
Nilsson Holguin
Keyword(s):  
Transcription Factor ◽  
Intervertebral Disc ◽  
Wnt Signaling ◽  
Cell Fate ◽  
Biomechanical Properties ◽  
Nucleus Pulposus Cells ◽  
Hypertrophic Chondrocyte ◽  
Age Related ◽  
Ivd Degeneration

ABSTRACTOsterix is a critical transcription factor of mesenchymal stem cell fate, where its loss or loss of WNT signaling diverts differentiation to a chondrocytic lineage. Intervertebral disc (IVD) degeneration activates differentiation of prehypertrophic chondrocyte-like cells and inactivates WNT signaling, but its interacting role with osterix is unclear. First, compared to young-adult (5mo), mechanical compression of old (18mo) IVD induced greater IVD degeneration. Aging (5 vs 12mo) and/or compression reduced the transcription of osterix and notochordal marker T by 40-75%. Compression elevated transcription of hypertrophic chondrocyte marker MMP13 and pre-osterix transcription factor RUNX2, but less so in 12mo IVD. Next, using an Ai9/td reporter and immunohistochemistry, annulus fibrosus and nucleus pulposus cells of 5mo IVD expressed osterix, but aging and compression reduced its expression. Lastly, in vivo LRP5-deficiency in osterix-expressing cells degenerated the IVD, inactivated WNT signaling, reduced the biomechanical properties by 45-70%, and reduced transcription of osterix, notochordal markers and chondrocytic markers by 60-80%. Overall, these data indicate that age-related inactivation of WNT signaling in osterix-expressing cells may limit regeneration by depleting progenitors and attenuating the expansion of chondrocyte-like cells.

In Vivo Administration of an Inflammatory Stimulant can Trigger Loss of Biomechanical and Biochemical Properties of the Intervertebral Disc

2012 ◽  
Author(s):  
Neena Rajan ◽  
Nate Stetson ◽  
Robert Maidhof ◽  
Mitchell Levine ◽  
Nadeen Chahine
Keyword(s):  
Intervertebral Disc ◽  
Morphological Changes ◽  
Direct Injection ◽  
Biomechanical Properties ◽  
Biochemical Properties ◽  
Post Injury ◽  
Sham Injection ◽  
Tnf Α ◽  
Ivd Degeneration

Human intervertebral disc (IVD) degeneration is accompanied by chronic inflammation, particularly seen in the elevated levels of pro-inflammatory cytokines IL-1β and TNF-α [1–3]. Animal models of disc degeneration (DD) using stab or laceration of the disc generally reproduce morphological changes of IVD degeneration. However, inflammatory changes in these models are thought to be acute and transient post injury [4–6]. The goal of this study is to explore the effect of direct inflammatory stimulation of the IVD on disc biochemical and biomechanical properties in vivo. We utilize lipopolysaccharide (LPS), an inflammatory stimulant that provokes secretion of multiple cytokines by disc cells. We have previously shown that direct injection of LPS into the disc results in significantly higher protein levels of IL-1β, TNF-α, HMGB-1 and MIF vs. sham injection up to 7 days post administration [7]. The goal of this study is to explore the dose-dependent response of this inflammatory stimulation on the biochemical and biomechanical properties of IVD in vivo. We hypothesize that LPS stimulation mimics the pathophysiology of DD by triggering a group of cytokines that are associated with IVD degeneration. LPS is administered using micro needles (<10% disc height) in order to minimize the potential disruption by needle injection.

scholarly journals Selection of the Optimal Puncture Needle for Induction of a Rat Intervertebral Disc Degeneration Model

2019 ◽  
Vol 4 (22;4) ◽  
pp. 353-360
Author(s):  
Jun Zou
Keyword(s):  
Animal Model ◽  
Intervertebral Disc ◽  
Optimal Choice ◽  
Mri Imaging ◽  
Needle Size ◽  
Puncture Needle ◽  
Model Study ◽  
Magnetic Resonance Imaging Mri ◽  
Underlying Mechanisms ◽  
Ivd Degeneration

Background: The incidence of intervertebral disc (IVD) degeneration has increased in recent years. A simple, reliable, and reproducible animal model is critical for understanding the underlying mechanisms of IVD degeneration. The caudal discs of rats have been proposed as a common puncture model in which to induce IVD degeneration. However, there is still no consensus on the size of needle to be used. Objectives: The present study aimed to identify the appropriate needle size to establish an IVD degeneration model. Study Design: A randomized, experimental trial. Setting: Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, China. Methods: Validity was verified by magnetic resonance imaging (MRI) and histology. Results: From T2-weighted MRI imaging and histological examination, the IVD punctured by the 16-gauge needle degenerated acutely one week after the operation, whereas the 26-gauge needle puncture did no harm to the IVD. An 18-gauge needle showed a progressive degeneration in IVD. Limitations: The observation period was not very long (4 weeks). Conclusions: An 18-gauge needle can be used to induce IVD degeneration in rats. Therefore, an 18-gauge needle is the optimal selection to establish the degenerative IVD model on rats, whereas the 26-gauge needle failed to cause IVD degeneration. Thus, to study the prevention and treatment of IVD degeneration, a 26-gauge needle can be used for IVD injection of growth factors, plasmids, and drugs. A 16-gauge needle may be used to induce acute disc injury, but not IVD degeneration. Key words: Low back pain, degenerative intervertebral disc, animal model, puncture needle, rat model, optimal choice

scholarly journals Influence of Angiopoietin Treatment with Hypoxia and Normoxia on Human Intervertebral Disc Progenitor Cell’s Proliferation, Metabolic Activity, and Phenotype

2021 ◽  
Vol 11 (15) ◽  
pp. 7144
Author(s):  
Muriel C. Bischof ◽  
Sonja Häckel ◽  
Andrea Oberli ◽  
Andreas S. Croft ◽  
Katharina A. C. Oswald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intervertebral Disc ◽  
Metabolic Activity ◽  
Cell Metabolism ◽  
Trauma Patients ◽  
Low Back ◽  
Relative Gene Expression ◽  
Progenitor Cell Population ◽  
Ivd Degeneration ◽  
Relative Gene

Increasing evidence implicates intervertebral disc (IVD) degeneration as a major contributor to low back pain. In addition to a series of pathogenic processes, degenerated IVDs become vascularized in contrast to healthy IVDs. In this context, angiopoietin (Ang) plays a crucial role and is involved in cytokine recruitment, and anabolic and catabolic reactions within the extracellular matrix (ECM). Over the last decade, a progenitor cell population has been described in the nucleus pulposus (NP) of the IVD to be positive for the Tie2 marker (also known as Ang-1 receptor). In this study, we investigated the influence of Ang-1 and Ang-2 on human NP cell (Tie2+, Tie2- or mixed) populations isolated from trauma patients during 7 days in normoxia (21% O2) or hypoxia (≤ 5% O2). At the end of the process, the proliferation and metabolic activity of the NP cells were analyzed. Additionally, the relative gene expression of NP-related markers was evaluated. NP cells showed a higher proliferation depending on the Ang treatment. Moreover, the study revealed higher NP cell metabolism when cultured in hypoxia. Additionally, the relative gene expression followed, with an increase linked to the oxygen level and Ang concentration. Our study comparing different NP cell populations may be the start of new approaches for the treatment of IVD degeneration.

scholarly journals The Myth of Fibroid Degeneration in the Canine Intervertebral Disc: A Histopathological Comparison of Intervertebral Disc Degeneration in Chondrodystrophic and Nonchondrodystrophic Dogs

2017 ◽  
Vol 54 (6) ◽  
pp. 945-952 ◽  
Author(s):  
Tove Hansen ◽  
Lucas A. Smolders ◽  
Marianna A. Tryfonidou ◽  
Björn P. Meij ◽  
Johannes C. M. Vernooij ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Histopathological Changes ◽  
Seminal Work ◽  
Notochordal Cells ◽  
Tissue Changes ◽  
Chondroid Metaplasia ◽  
Ivd Degeneration

Since the seminal work by Hans-Jörgen Hansen in 1952, it has been assumed that intervertebral disc (IVD) degeneration in chondrodystrophic (CD) dogs involves chondroid metaplasia of the nucleus pulposus, whereas in nonchondrodystrophic (NCD) dogs, fibrous metaplasia occurs. However, more recent studies suggest that IVD degeneration in NCD and CD dogs is more similar than originally thought. Therefore, the aim of this study was to compare the histopathology of IVD degeneration in CD and NCD dogs. IVDs with various grades of degeneration (Thompson grade I–III, n = 7 per grade) from both CD and NCD dogs were used (14 CD and 18 NCD dogs, 42 IVDs in total). Sections were scored according to a histological scoring scheme for canine IVD degeneration, including evaluation of the presence of fibrocyte-like cells in the nucleus pulposus. In CD dogs, the macroscopically non-degenerated nucleus pulposus contained mainly chondrocyte-like cells, whereas the non-degenerated nucleus pulposus of NCD dogs mainly contained notochordal cells. The histopathological changes in degenerated discs were similar in CD and NCD dogs and resembled chondroid metaplasia. Fibrocytes were not seen in the nucleus pulposus, indicating that fibrous degeneration of the IVD was not present in any of the evaluated grades of degeneration. In conclusion, intervertebral disc degeneration was characterized by chondroid metaplasia of the nucleus pulposus in both NCD and CD dogs. These results revoke the generally accepted concept that NCD and CD dogs suffer from a different type of IVD degeneration, in veterinary literature often referred to as chondroid or fibroid degeneration, and we suggest that chondroid metaplasia should be used to describe the tissue changes in the IVD in both breed types.

scholarly journals Computational Modeling Intervertebral Disc Pathophysiology: A Review

2022 ◽  
Vol 12 ◽  
Author(s):  
Mallory Volz ◽  
Shady Elmasry ◽  
Alicia R. Jackson ◽  
Francesco Travascio
Keyword(s):  
Intervertebral Disc ◽  
Computational Modeling ◽  
Medical Condition ◽  
Primary Source ◽  
Special Focus ◽  
Biochemical Alterations ◽  
Wide Range ◽  
Mechanical Factors ◽  
Ivd Degeneration ◽  
Physical Changes

Lower back pain is a medical condition of epidemic proportion, and the degeneration of the intervertebral disc has been identified as a major contributor. The etiology of intervertebral disc (IVD) degeneration is multifactorial, depending on age, cell-mediated molecular degradation processes and genetics, which is accelerated by traumatic or gradual mechanical factors. The complexity of such intertwined biochemical and mechanical processes leading to degeneration makes it difficult to quantitatively identify cause–effect relationships through experiments. Computational modeling of the IVD is a powerful investigative tool since it offers the opportunity to vary, observe and isolate the effects of a wide range of phenomena involved in the degenerative process of discs. This review aims at discussing the main findings of finite element models of IVD pathophysiology with a special focus on the different factors contributing to physical changes typical of degenerative phenomena. Models presented are subdivided into those addressing role of nutritional supply, progressive biochemical alterations stemming from an imbalance between anabolic and catabolic processes, aging and those considering mechanical factors as the primary source that induces morphological change within the disc. Limitations of the current models, as well as opportunities for future computational modeling work are also discussed.

scholarly journals Denosumab Alleviates Intervertebral Disc Degeneration Adjacent to a Lumbar Fusion by Inhibiting Endplate Osteochondral Remodeling and Vertebral Osteoporosis in Ovariectomized Rats

2020 ◽  
Author(s):  
Qi Sun ◽  
Fa-Ming Tian ◽  
Fang Liu ◽  
Jia-Kang Fang ◽  
Yun-Peng Hu ◽  
...  
Keyword(s):  
Bone Formation ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Lumbar Fusion ◽  
Biomechanical Properties ◽  
Disc Height ◽  
X Ray ◽  
Manual Palpation ◽  
Trap Staining

Abstract Background: Although adjacent segmental intervertebral disc degeneration (ASDD) is one of the most common complications after lumbar fusion, its exact mechanism remains unclear. As an antibody to RANKL, denosumab (Dmab) effectively reduces bone resorption and stimulates bone formation, which can increase bone mineral density (BMD) and improve osteoporosis. However, it has not been confirmed whether Dmab has a reversing or retarding effect on ASDD. Methods: Three-month-old female Sprague-Dawley rats that underwent L4–L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation four weeks after OVX surgery were given Dmab four weeks after PLF surgery (OVX+PLF+Dmab group). In addition, the following control groups were defined: Sham, OVX, PLF, and OVX+PLF (n=12 each).Then, manual palpation and X-ray were used to evaluate the state of lumbar fusion. The bone microstructure in the lumbar vertebra and endplate as well as the disc height index (DHI) of the L5/6 were evaluated by microcomputed tomography (μCT). The characteristic alterations of ASDD were identified via Safranin-O green staining staining. Osteoclasts were detected using tartrate-resistant acid phosphatase (TRAP) staining and the biomechanical properties of vertebra were evaluated. Aggrecan (Agg), metalloproteinase-13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) expression in the intervertebral disc were detected by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) analysis.Results: Manual palpation showed clear evidence of the fused segment’s immobility. Compared to the OVX+PLF group, more new bone formation was observed by X-ray examination in the OVX+PLF+Dmab group. Dmab significantly alleviated ASDD by retaining disc height index (DHI), decreasing porosity of endplate, and increasing the biomechanical properties and BMD of vertebra. TRAP staining results showed a significantly decreased number after Dmab treatment, especially in subchondral bone and cartilaginous endplate. Moreover, the results of protein and mRNA expression in intervertebral disc (IVD) showed that Dmab not only inhibited matrix degradation by decreasing MMP-13 and ADAMTS-4 but also promoted matrix synthesis by increasing Agg. Conclusions: These results suggest that Dmab may be a novel therapeutic target for the treatment of ASDD.

scholarly journals Reactive Oxygen Species Mediate Low Back Pain by Upregulating Substance P in Intervertebral Disc Degeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jiancheng Zheng ◽  
Jian Zhang ◽  
Xingkai Zhang ◽  
Zhiping Guo ◽  
Wenjian Wu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Low Back Pain ◽  
Back Pain ◽  
Substance P ◽  
Intervertebral Disc ◽  
Reactive Oxygen ◽  
Alternative Methods ◽  
Low Back ◽  
Oxygen Species ◽  
Ivd Degeneration

Reactive oxygen species (ROS) are thought to have a strong correlation with a number of intervertebral disc (IVD) diseases. Here, we aimed to determine whether ROS represent an etiology of low back pain (LBP) during IVD degeneration. Thirty degenerated intervertebral disc samples were obtained from patients, and ROS levels were quantified using dihydroethidium (DHE) staining. The results suggested a significant correlation between the ROS level and the severity of LBP. Subsequently, a puncture-induced LBP model was established in rats, and ROS levels significantly increased compared with those in the sham surgery group, accompanied with severe puncture-induced IVD degeneration. In addition, when ROS levels were increased by H2O2 administration or decreased by NAC treatment, the rats showed increased or decreased LBP, respectively. Based on this evidence, we further determined that stimulation with H2O2 in nucleus pulposus cells (NPCs) in vivo or in vitro resulted in upregulation of substance P (SP), a peptide thought to be involved in the synaptic transmission of pain, and that the severity of LBP decreased when SP levels were increased by exogenous SP administration or neutralized via aprepitant treatment in the IVDs of rats. In conclusion, ROS are primary inducers of LBP based on clinical and animal data, and the mechanism involves ROS stimulation of NPCs to secrete SP, which is a critical neurotransmitter peptide, to promote LBP in IVDs. Therefore, reducing the level of ROS with specific drugs and inhibiting SP may be alternative methods to treat LBP in the clinic.

Whole-body Vibration Attenuates Pyroptosis-Mediated Inflammation but Accelerates Progression of Intervertebral Disc Degeneration

2020 ◽  
Author(s):  
Fang-da Fu ◽  
Sai Yao ◽  
Zhi-tao Sun ◽  
Cheng-cong Zhou ◽  
Huan Yu ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Whole Body Vibration ◽  
Sensory Nerves ◽  
Sensory Innervation ◽  
Whole Body ◽  
Body Vibration ◽  
Pharmaceutical Therapy ◽  
The Matrix ◽  
Matrix Metabolism ◽  
Ivd Degeneration

Abstract Background Whole body vibration (WBV) is a non-pharmaceutical therapy that has been widely incorporated into clinical practice for musculoskeletal disorders, including low back pain (LBP). Intervertebral disc (IVD) degeneration (IVDD) is clinically associated with LBP and is known as the main cause for LBP. However, cumulative evidence also suggested WBV might have an adverse impact on IVDs. Moreover, previous studies have been focusing on the effects of WBV on healthy mice, rather than those suffering from IVDD. Thus, uncertainties still exist concerning the effects of WBV on IVDs undergoing IVDD. This study was aiming to evaluate the effects of WBV intervention on the development and progression of IVDD mouse model induced by lumbar spine instability (LSI) surgery. Methods LSI surgery, by resecting the lumbar 3 rd -5 th spinous processes along with the supraspinous and interspinous ligaments, was conducted in 10-week-old male mice which then received WBV treatment (1 h per day, 5 days per week, at 3 Hz with peak acceleration at 0.4 g) or sham treatment. The progression of IVDD was evaluated by MRI, μCT and histological analyses after WBV treatment. The matrix metabolism, distribution of sensory nerves, pyroptosis in IVDs tissues were determined by immunohistological analysis or real-time PCR. The apoptosis of IVD cells was detected by TUNEL assay. Results LSI surgery was successful in producing IVDD modeling. WBV caused decreases in IVD height and annulus fibrosus (AF) score, as well as increased numbers of apoptotic cells in IVD tissues. WBV contributed to sensory innervation into AF and upregulation of Adamts5 and MMP3 expression in IVDD mice received LSI surgery. In addition, WBV treatment triggered earlier activation of Wnt/β-catenin signaling in IVDD mice with WBV treatment compared with those without WBV treatment. Unexpectedly, WBV significantly attenuated Caspase-1 and IL-1β expression in AF. Conclusions Collectively, our findings demonstrate that WBV treatment may worsen the development of ongoing IVDD. Decrease of IL-1β expression after WBV intervention may partially account for patient self-reported pain relief after WBV treatment in some previous trials. This study may help us better understand the effects of WBV intervention on patients experiencing LBP resulting from the degeneration of lumbar IVDs.

scholarly journals Caspase-3 knockout inhibits intervertebral disc degeneration related to injury but accelerates degeneration related to aging

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takashi Ohnishi ◽  
Katsuhisa Yamada ◽  
Koji Iwasaki ◽  
Takeru Tsujimoto ◽  
Hideaki Higashi ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Intervertebral Disc Degeneration ◽  
Caspase 3 ◽  
Treatment Target ◽  
Age Related ◽  
Different Types ◽  
New Treatments ◽  
Surgical Treatments ◽  
Ivd Degeneration ◽  
Primary Effector

AbstractApproximately 40% of people under 30 and over 90% of people 55 or older suffer from moderate-to-severe levels of degenerative intervertebral disc (IVD) disease in their lumbar spines. Surgical treatments are sometimes effective; however, the treatment of back pain related to IVD degeneration is still a challenge; therefore, new treatments are necessary. Apoptosis may be important in IVD degeneration because suppressing cell apoptosis inside the IVD inhibits degeneration. Caspase-3, the primary effector of apoptosis, may be a key treatment target. We analyzed caspase-3’s role in two different types of IVD degeneration using caspase-3 knockout (Casp-3 KO) mice. Casp-3 KO delayed IVD degeneration in the injury-induced model but accelerated it in the age-induced model. Our results suggest that this is due to different pathological mechanisms of these two types of IVD degeneration. Apoptosis was suppressed in the IVD cells of Casp-3 KO mice, but cellular senescence was enhanced. This would explain why the Casp-3 KO was effective against injury-induced, but not age-related, IVD degeneration. Our results suggest that short-term caspase-3 inhibition could be used to treat injury-induced IVD degeneration.

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