Joshua Kelley, Nathan Buchweitz, Avery Madden, Hongming Fan, Glenn Hepfer, Michael Kern, Danyelle M. Townsend, Tong Ye, Hai Yao, Yongren Wu
Background
Cigarette smoking is a recognized risk factor for orthopedic disorders, particularly intervertebral disc (IVD) degenerative disease. However, the IVD pathophysiology, especially the spatial–temporal remodeling progression in the context of cigarette smoking, remains unclear. This study aimed to address this knowledge gap through a quantitative assessment of IVD structural composition and diffusion properties using a Sprague–Dawley rat model.
Methods
Twenty-four rats were divided into control and smoke exposure cohorts, each with two sub-groups of six rats. One smoke exposure sub-group was sacrificed after 2 months of daily cigarette smoke exposure in a custom smoking apparatus, while the other was sacrificed after an additional 5 months of smoke cessation. The control groups were age-matched to the smoke exposure groups. A fluorescent recovery after photobleaching (FRAP) technique was used to determine solute diffusivities and multi-photon excitation (MPE) imaging was performed to characterize structural changes in the annulus fibrosus (AF), nucleus pulposus (NP), and cartilage endplate (CEP).
Results
A decrease in diffusivity was observed in the CEP and the AF (radial direction only) after 2 months of smoke exposure. MPE imaging showed aberrant CEP calcification and reduced AF radial collagen fiber bundle diameter, suggesting that the IVD exhibits regionally dependent structural remodeling due to smoke exposure. Furthermore, the smoke cessation group showed deteriorating alterations of structure and diffusivities in all three-disc regions, including the NP, indicating that five-month smoke cessation alone didn't reverse the progression of IVD degenerative remodeling during aging.
Conclusion
This study advances the understanding of IVD pathophysiology in the context of cigarette smoke exposure and cessation, laying the groundwork for potential earlier diagnosis and optimized interventions.
{"title":"Effect of cigarette smoke exposure and cessation on regional diffusion properties in rat intervertebral discs","authors":"Joshua Kelley, Nathan Buchweitz, Avery Madden, Hongming Fan, Glenn Hepfer, Michael Kern, Danyelle M. Townsend, Tong Ye, Hai Yao, Yongren Wu","doi":"10.1002/jsp2.70015","DOIUrl":"10.1002/jsp2.70015","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cigarette smoking is a recognized risk factor for orthopedic disorders, particularly intervertebral disc (IVD) degenerative disease. However, the IVD pathophysiology, especially the spatial–temporal remodeling progression in the context of cigarette smoking, remains unclear. This study aimed to address this knowledge gap through a quantitative assessment of IVD structural composition and diffusion properties using a Sprague–Dawley rat model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty-four rats were divided into control and smoke exposure cohorts, each with two sub-groups of six rats. One smoke exposure sub-group was sacrificed after 2 months of daily cigarette smoke exposure in a custom smoking apparatus, while the other was sacrificed after an additional 5 months of smoke cessation. The control groups were age-matched to the smoke exposure groups. A fluorescent recovery after photobleaching (FRAP) technique was used to determine solute diffusivities and multi-photon excitation (MPE) imaging was performed to characterize structural changes in the annulus fibrosus (AF), nucleus pulposus (NP), and cartilage endplate (CEP).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A decrease in diffusivity was observed in the CEP and the AF (radial direction only) after 2 months of smoke exposure. MPE imaging showed aberrant CEP calcification and reduced AF radial collagen fiber bundle diameter, suggesting that the IVD exhibits regionally dependent structural remodeling due to smoke exposure. Furthermore, the smoke cessation group showed deteriorating alterations of structure and diffusivities in all three-disc regions, including the NP, indicating that five-month smoke cessation alone didn't reverse the progression of IVD degenerative remodeling during aging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study advances the understanding of IVD pathophysiology in the context of cigarette smoke exposure and cessation, laying the groundwork for potential earlier diagnosis and optimized interventions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shiva S. Tripathi, Robert Sneath, Aprajay Golash, Parag Desai, Duncan McHale, Sarah Guest, Charlie Brindley, Paul Cummings, Shane Smith, Conrad Stroud, Graham Scott, Steve Ruston, Lloyd Czaplewski
Background
Bacterial infection of the intervertebral disc is difficult to treat because the tissue is usually not vascularized and systemic antibiotic therapy may not reach optimal antibacterial exposure. Here we characterize the safety, tolerability, and pharmacokinetics of PP353, a suspension of micronized linezolid, formulated for direct intervertebral disc administration.
Methods
The safety, tolerability, and pharmacokinetics of an intradiscal administration of PP353, was assessed in Part A of a Phase 1b study and consisted of a single injection of study drug (3 mL of PP353 and 150 mg linezolid). Clinical assessment included initial safety and tolerability of PP353 with continued follow-up for 12 months. Assessment of linezolid concentration in plasma samples enabled characterization of the pharmacokinetics. Deconvolution of systemic linezolid was used to estimate intervertebral disc linezolid concentration.
Results
Intradiscal administration of 3 mL of PP353 (linezolid 50 mg/mL) to the nucleus pulposus was well tolerated with no reported study treatment-related severe or serious adverse events and resulted in an average geometric mean linezolid plasma Cmax of 1300 ng/mL at 7.27 h post-administration. The linezolid plasma Cmax observed with intradiscal PP353 is approximately 10% that observed with a standard oral or iv administration of 600 mg linezolid. Pharmacokinetic deconvolution estimated that a single dose of PP353 (150 mg linezolid) provided intradiscal bactericidal concentration of linezolid for 96 h and bacteriostatic exposure for up to 120 h after dosing.
Conclusion
Intradiscal administration of 3 mL of PP353 is well-tolerated and based on the pharmacokinetics following a single injection, a two-dose regimen of PP353 (150 mg linezolid) on Day 1 and Day 5 ± 1 was selected to explore safety, tolerability, pharmacokinetics, and efficacy in Part B of the Persica 002 study.
{"title":"Pharmacokinetics of PP353, a formulation of linezolid for intervertebral disc administration, in patients with chronic low back pain and Modic change Type 1: A first-in-human, Phase 1b, open-label, single-dose study","authors":"Shiva S. Tripathi, Robert Sneath, Aprajay Golash, Parag Desai, Duncan McHale, Sarah Guest, Charlie Brindley, Paul Cummings, Shane Smith, Conrad Stroud, Graham Scott, Steve Ruston, Lloyd Czaplewski","doi":"10.1002/jsp2.70009","DOIUrl":"10.1002/jsp2.70009","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Bacterial infection of the intervertebral disc is difficult to treat because the tissue is usually not vascularized and systemic antibiotic therapy may not reach optimal antibacterial exposure. Here we characterize the safety, tolerability, and pharmacokinetics of PP353, a suspension of micronized linezolid, formulated for direct intervertebral disc administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The safety, tolerability, and pharmacokinetics of an intradiscal administration of PP353, was assessed in Part A of a Phase 1b study and consisted of a single injection of study drug (3 mL of PP353 and 150 mg linezolid). Clinical assessment included initial safety and tolerability of PP353 with continued follow-up for 12 months. Assessment of linezolid concentration in plasma samples enabled characterization of the pharmacokinetics. Deconvolution of systemic linezolid was used to estimate intervertebral disc linezolid concentration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Intradiscal administration of 3 mL of PP353 (linezolid 50 mg/mL) to the nucleus pulposus was well tolerated with no reported study treatment-related severe or serious adverse events and resulted in an average geometric mean linezolid plasma <i>C</i><sub>max</sub> of 1300 ng/mL at 7.27 h post-administration. The linezolid plasma <i>C</i><sub>max</sub> observed with intradiscal PP353 is approximately 10% that observed with a standard oral or iv administration of 600 mg linezolid. Pharmacokinetic deconvolution estimated that a single dose of PP353 (150 mg linezolid) provided intradiscal bactericidal concentration of linezolid for 96 h and bacteriostatic exposure for up to 120 h after dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Intradiscal administration of 3 mL of PP353 is well-tolerated and based on the pharmacokinetics following a single injection, a two-dose regimen of PP353 (150 mg linezolid) on Day 1 and Day 5 ± 1 was selected to explore safety, tolerability, pharmacokinetics, and efficacy in Part B of the Persica 002 study.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Graham Hagger, Sarah Guest, Stephen Birchall, Alys Bradley, Charlie Brindley, David Corbett, Paul J. Cummings, Cristina Freire, James Harris, Andrew Wise, Melanie Wood, Lloyd G. Czaplewski
Introduction
Bacterial infection of the intervertebral disc can lead to vertebral endplate edema known as Modic changes, with associated chronic low back pain. Oral antimicrobial therapy has shown efficacy but relies on prolonged dosing and may not be optimal in terms of patient outcome, side effects, or antibiotic stewardship. There is no antibiotic formulation approved for intradiscal administration. Here, we describe the development and preclinical characterization of a formulation of linezolid, a suspension of 50 mg/mL micronized powder, for intradiscal administration.
Methods
Micronization, particle size analysis, Franz cell diffusion assays, ex vivo bioassay, and estimates of gelling temperature were used to optimize the composition and properties of the formulation. Performance of the formulation was assessed using sheep to characterize the pharmacokinetics and a model of intradiscal infection was developed to demonstrate efficacy. Suitability for human administration was demonstrated in a Good Laboratory Practice (GLP) local tolerance study.
Results
Micronized linezolid, formulated as a powder suspension using a vehicle containing poloxamer 407 and iohexol, provided a temperature-dependent radio-opaque gel that was suitable for image-guided percutaneous intradiscal administration. Efficacy in a sheep model of intradiscal Staphylococcus aureus infection was demonstrated. The formulation provides a high level of sheep disc tissue exposure, with Cmax of 6500 μg/g and limited systemic exposure, with a plasma Cmax of 0.04 μg/mL per 0.1 mL dose (5 mg of linezolid). Deconvolution of plasma linezolid pharmacokinetics correlated with linezolid remaining in the disc over time. Observations from a GLP local tolerance study with the linezolid formulation were of a minor nature and related to the intradiscal administration procedure.
Conclusions
Linezolid can be formulated for image-guided percutaneous intradiscal administration. The formulation is now in a Phase 1b clinical trial to evaluate safety, pharmacokinetics, and efficacy in patients with CLBP and suspected bacterial infection.
{"title":"Preclinical development and characterisation of PP353, a formulation of linezolid for intradiscal administration","authors":"Graham Hagger, Sarah Guest, Stephen Birchall, Alys Bradley, Charlie Brindley, David Corbett, Paul J. Cummings, Cristina Freire, James Harris, Andrew Wise, Melanie Wood, Lloyd G. Czaplewski","doi":"10.1002/jsp2.70010","DOIUrl":"10.1002/jsp2.70010","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Bacterial infection of the intervertebral disc can lead to vertebral endplate edema known as Modic changes, with associated chronic low back pain. Oral antimicrobial therapy has shown efficacy but relies on prolonged dosing and may not be optimal in terms of patient outcome, side effects, or antibiotic stewardship. There is no antibiotic formulation approved for intradiscal administration. Here, we describe the development and preclinical characterization of a formulation of linezolid, a suspension of 50 mg/mL micronized powder, for intradiscal administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Micronization, particle size analysis, Franz cell diffusion assays, ex vivo bioassay, and estimates of gelling temperature were used to optimize the composition and properties of the formulation. Performance of the formulation was assessed using sheep to characterize the pharmacokinetics and a model of intradiscal infection was developed to demonstrate efficacy. Suitability for human administration was demonstrated in a Good Laboratory Practice (GLP) local tolerance study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Micronized linezolid, formulated as a powder suspension using a vehicle containing poloxamer 407 and iohexol, provided a temperature-dependent radio-opaque gel that was suitable for image-guided percutaneous intradiscal administration. Efficacy in a sheep model of intradiscal <i>Staphylococcus aureus</i> infection was demonstrated. The formulation provides a high level of sheep disc tissue exposure, with C<sub>max</sub> of 6500 μg/g and limited systemic exposure, with a plasma C<sub>max</sub> of 0.04 μg/mL per 0.1 mL dose (5 mg of linezolid). Deconvolution of plasma linezolid pharmacokinetics correlated with linezolid remaining in the disc over time. Observations from a GLP local tolerance study with the linezolid formulation were of a minor nature and related to the intradiscal administration procedure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Linezolid can be formulated for image-guided percutaneous intradiscal administration. The formulation is now in a Phase 1b clinical trial to evaluate safety, pharmacokinetics, and efficacy in patients with CLBP and suspected bacterial infection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, and apoptosis plays a key role in its pathogenesis. Distal-less homeobox 5 (Dlx5) has been reported to induce cell apoptosis. Melatonin, as a powerful antiapoptotic agent, has been widely reported.
Aim
This study aimed to investigate the role of DLX5 in the pathogenesis of IVDD and the potential therapeutic role of melatonin in targeting DLX5 in IVDD.
Materials & Methods
Western blotting, RT–qPCR, immunohistochemistry, si-DLX5, Ex-DLX5, flow cytometry, and immunofluorescence were used to examine the regulatory effect of DLX5 on apoptosis. Therapeutic efficacy was assessed by the intraperitoneal injection of melatonin into IVDD mice.
Results
The expression level of DLX5 is significantly increased in IVDD, and the expression levels were positively correlated with the grade of IVDD. DLX5 was significantly upregulated in TNF-α-induced degenerative NP cells. Degenerative NP cells transfected with si-DLX5 exhibited significantly less apoptosis than control cells. Melatonin significantly alleviated IVDD in surgically induced IVDD model mice.
Discussion
The results revealed that the expression of DLX5 was positively correlated with the severity of IVDD and that melatonin ameliorated DLX5-induced apoptosis and extracellular matrix imbalance by inhibiting the TGF-β/Smad signaling pathway. This study may provide therapeutic strategies to alleviate inflammation-induced apoptosis IVDD-associated inflammation-induced apoptosis.
Conclusion
DLX5 plays an important role in IVDD progression by promoting apoptosis, and melatonin represents a promising therapeutic strategy for alleviating IVDD-associated inflammation and apoptosis.
{"title":"Melatonin attenuates degenerative disc degression by downregulating DLX5 via the TGF/Smad2/3 pathway in nucleus pulposus cells","authors":"Kuibo Zhang, Hua Wang, Ling Mo, Xiaohui Huang, Chao Yuan, Caijun Liu","doi":"10.1002/jsp2.70014","DOIUrl":"10.1002/jsp2.70014","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, and apoptosis plays a key role in its pathogenesis. Distal-less homeobox 5 (Dlx5) has been reported to induce cell apoptosis. Melatonin, as a powerful antiapoptotic agent, has been widely reported.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study aimed to investigate the role of DLX5 in the pathogenesis of IVDD and the potential therapeutic role of melatonin in targeting DLX5 in IVDD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials & Methods</h3>\u0000 \u0000 <p>Western blotting, RT–qPCR, immunohistochemistry, si-DLX5, Ex-DLX5, flow cytometry, and immunofluorescence were used to examine the regulatory effect of DLX5 on apoptosis. Therapeutic efficacy was assessed by the intraperitoneal injection of melatonin into IVDD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The expression level of DLX5 is significantly increased in IVDD, and the expression levels were positively correlated with the grade of IVDD. DLX5 was significantly upregulated in TNF-α-induced degenerative NP cells. Degenerative NP cells transfected with si-DLX5 exhibited significantly less apoptosis than control cells. Melatonin significantly alleviated IVDD in surgically induced IVDD model mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>The results revealed that the expression of DLX5 was positively correlated with the severity of IVDD and that melatonin ameliorated DLX5-induced apoptosis and extracellular matrix imbalance by inhibiting the TGF-β/Smad signaling pathway. This study may provide therapeutic strategies to alleviate inflammation-induced apoptosis IVDD-associated inflammation-induced apoptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>DLX5 plays an important role in IVDD progression by promoting apoptosis, and melatonin represents a promising therapeutic strategy for alleviating IVDD-associated inflammation and apoptosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li Li, Hadil Al-Jallad, Aiwei Sun, Miltiadis Georgiopoulos, Rakan Bokhari, Jean Ouellet, Peter Jarzem, Hosni Cherif, Lisbet Haglund
Background
Extracellular vesicles (EVs) function as biomarkers and are crucial in cell communication and regulation, with therapeutic potential for intervertebral disc (IVD)-related low back pain (LBP). EV cargo is often affected by tissue health, which may affect the therapeutic potential. There is currently limited knowledge of how the cargo of IVD cell-derived EVs varies with tissue health and how differences in proteomic profile affect the predicted biological functions.
Methods
Our study purified EVs from human IVD cell conditioned media by size-exclusion chromatography. Nanoparticle tracking analysis was conducted to measure EV size and concentration. Transmission electron microscopy and Western blot were performed to examine EV structure and markers. Tandem mass tag-mass spectrometry was conducted to determine protein cargo.
Results
Most EVs were exosomes and intermediate microvesicles with an increasing amount linked to disease progression. Of the proteins detected, 88.6% were shared across the non-degenerate, mildly-degenerate, and degenerate samples. GO and KEGG analyses revealed that cargo from the mildly-degenerate samples was the most distinct, with the proteins in high abundance strongly associated with extracellular matrix (ECM) organization and structure. Shared proteins, highly expressed in the non-degenerate and degenerate samples, showed strong associations with cell adhesion, ECM–receptor interaction, and vesicle-mediated transport, respectively.
Conclusions
Our findings indicate that EVs from IVD cells from tissue with different degrees of degeneration share a majority of the cargo proteins. However, the level of expression differs with degeneration grade. Cargo from the mildly-degenerate samples exhibits the most differences. A better understanding of changes in EV cargo in the degenerative process may provide novel information related to molecular mechanisms underlying IVD degeneration and suggest new potential treatment modalities for IVD-related LBP.
{"title":"The proteomic landscape of extracellular vesicles derived from human intervertebral disc cells","authors":"Li Li, Hadil Al-Jallad, Aiwei Sun, Miltiadis Georgiopoulos, Rakan Bokhari, Jean Ouellet, Peter Jarzem, Hosni Cherif, Lisbet Haglund","doi":"10.1002/jsp2.70007","DOIUrl":"10.1002/jsp2.70007","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Extracellular vesicles (EVs) function as biomarkers and are crucial in cell communication and regulation, with therapeutic potential for intervertebral disc (IVD)-related low back pain (LBP). EV cargo is often affected by tissue health, which may affect the therapeutic potential. There is currently limited knowledge of how the cargo of IVD cell-derived EVs varies with tissue health and how differences in proteomic profile affect the predicted biological functions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Our study purified EVs from human IVD cell conditioned media by size-exclusion chromatography. Nanoparticle tracking analysis was conducted to measure EV size and concentration. Transmission electron microscopy and Western blot were performed to examine EV structure and markers. Tandem mass tag-mass spectrometry was conducted to determine protein cargo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Most EVs were exosomes and intermediate microvesicles with an increasing amount linked to disease progression. Of the proteins detected, 88.6% were shared across the non-degenerate, mildly-degenerate, and degenerate samples. GO and KEGG analyses revealed that cargo from the mildly-degenerate samples was the most distinct, with the proteins in high abundance strongly associated with extracellular matrix (ECM) organization and structure. Shared proteins, highly expressed in the non-degenerate and degenerate samples, showed strong associations with cell adhesion, ECM–receptor interaction, and vesicle-mediated transport, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings indicate that EVs from IVD cells from tissue with different degrees of degeneration share a majority of the cargo proteins. However, the level of expression differs with degeneration grade. Cargo from the mildly-degenerate samples exhibits the most differences. A better understanding of changes in EV cargo in the degenerative process may provide novel information related to molecular mechanisms underlying IVD degeneration and suggest new potential treatment modalities for IVD-related LBP.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weishi Liang, Duan Sun, Bo Han, Yihan Yang, Peng Yin, Yong Hai
Background
Hybrid surgery (HS) combined cervical disc arthroplasty (CDA) with anterior cervical discectomy and fusion (ACDF) is emerging, but its biomechanical effects as a revision surgery (RS) on adjacent segments were unclear.
Objectives
This finite element (FE) study aimed to investigate the biomechanical characteristics of HS to treat two-level discontinuous ASD in ACDF RS.
Methods
A C2-T1 intact FE model was established and modified to a primary C5/6 ACDF model and five RS models. These RS models' segments C4/5 and C6/7 were revised using cage plus plate (C), zero-profile devices (P), and Bryan disc (D), respectively, generating C-C-C, P-C-P, D-C-P, P-C-D, and D-C-D models. In the intact and C5/6 ACDF models, a 1.0 Nm moment was used to produce the range of motion (ROM). A displacement load was applied to all RS models, to achieve a total ROM match that of the primary C5/6 ACDF model.
Results
In the P-C-P model, biomechanical responses including ROM, Intradiscal pressure (IDP), Facet joint force (FJF), and Maximum von Mises stresses of discs at segments C3/4 and C7/T1 were slightly lower than the C-C-C model. The biomechanical response parameters at segments C3/4 and C7/T1 of P-C-D, D-C-P, and D-C-D were smaller than those in C-C-C and P-C-P models. D-C-D had the most significant effect on reducing all biomechanical responses among all RS models in segments C3/4 and C7/T1. Moreover, the disc stress cloud maps showed that the maximum von Mises stress of the C3/4 disc was higher than that of C7/T1.
Conclusions
D-C-D, P-C-D, and D-C-P are good RS choices for reducing the biomechanical responses, and D-C-D was the best choice. P-C-P can be the best recommendation when it does not meet the CDA indications. This study provided a biomechanical reference for hybrid surgical decision-making in the ACDF RS for preventing ASD recurrence.
{"title":"Finite element analysis of two-level discontinuous cervical hybrid revision surgery strategy to reduce biomechanical responses of adjacent segments","authors":"Weishi Liang, Duan Sun, Bo Han, Yihan Yang, Peng Yin, Yong Hai","doi":"10.1002/jsp2.70008","DOIUrl":"10.1002/jsp2.70008","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hybrid surgery (HS) combined cervical disc arthroplasty (CDA) with anterior cervical discectomy and fusion (ACDF) is emerging, but its biomechanical effects as a revision surgery (RS) on adjacent segments were unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This finite element (FE) study aimed to investigate the biomechanical characteristics of HS to treat two-level discontinuous ASD in ACDF RS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A C2-T1 intact FE model was established and modified to a primary C5/6 ACDF model and five RS models. These RS models' segments C4/5 and C6/7 were revised using cage plus plate (C), zero-profile devices (P), and Bryan disc (D), respectively, generating C-C-C, P-C-P, D-C-P, P-C-D, and D-C-D models. In the intact and C5/6 ACDF models, a 1.0 Nm moment was used to produce the range of motion (ROM). A displacement load was applied to all RS models, to achieve a total ROM match that of the primary C5/6 ACDF model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the P-C-P model, biomechanical responses including ROM, Intradiscal pressure (IDP), Facet joint force (FJF), and Maximum von Mises stresses of discs at segments C3/4 and C7/T1 were slightly lower than the C-C-C model. The biomechanical response parameters at segments C3/4 and C7/T1 of P-C-D, D-C-P, and D-C-D were smaller than those in C-C-C and P-C-P models. D-C-D had the most significant effect on reducing all biomechanical responses among all RS models in segments C3/4 and C7/T1. Moreover, the disc stress cloud maps showed that the maximum von Mises stress of the C3/4 disc was higher than that of C7/T1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>D-C-D, P-C-D, and D-C-P are good RS choices for reducing the biomechanical responses, and D-C-D was the best choice. P-C-P can be the best recommendation when it does not meet the CDA indications. This study provided a biomechanical reference for hybrid surgical decision-making in the ACDF RS for preventing ASD recurrence.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jan Ulrich Jansen, Laura Zengerle, Marcel Steiner, Vincenza Sciortino, Marianna Tryfonidou, Hans-Joachim Wilke
Background
Often after large animal experiments in spinal research, the question arises—histology or biomechanics? While biomechanics are essential for informed decisions on the functionality of the therapy being studied, scientists often choose histological analysis alone. For biomechanical testing, for example, flexibility, specimens must be shipped to institutions with special testing equipment, as spine testers are complex and immobile. The specimens must usually be shipped frozen, and, thus, biological and histological investigations are not possible anymore. To allow both biomechanical and biological investigations with the same specimen and, thus, to reduce the number of required animals, the aim of the study was to develop a spine tester that can be shipped worldwide to test on-site.
Methods
The “Spine Tester TO GO” was designed consisting of a frame with three motors that initiate pure moments and rotate the specimen in three motion planes. A load cell and an optical motion tracking system controlled the applied loads and measured range of motion (ROM) and neutral zone (NZ). As a proof of concept, the new machine was validated and compared under real experimental conditions with an existing testing machine already validated employing fresh bovine tail discs CY34 (n = 10).
Results
The new spine tester measured reasonable ROM and NZ from hysteresis curves, and the ROM of the two testing machines formed a high coefficient of determination R2 = 0.986. However, higher ROM results of the new testing machine might be explained by the lower friction of the air bearings, which allowed more translational motion.
Conclusions
The spine tester TO GO now opens up new opportunities for on-site flexibility tests and contributes hereby to the 3R principle by limiting the number of experimental animals needed to obtain full characterization of spine units at the macroscopic, biomechanical, biochemical, and histological level.
背景：脊柱研究中的大型动物实验后往往会出现这样的问题--组织学还是生物力学？虽然生物力学对于决定所研究疗法的功能性至关重要，但科学家们往往只选择组织学分析。要进行生物力学测试，例如柔韧性测试，标本必须运到拥有特殊测试设备的机构，因为脊柱测试仪既复杂又不能移动。标本通常必须冷冻运输，因此无法再进行生物和组织学研究。为了用同一标本进行生物力学和生物学研究，从而减少所需动物的数量，本研究的目的是开发一种可运往世界各地进行现场测试的脊柱测试仪：脊柱测试仪 TO GO "由一个框架和三个电机组成，三个电机可启动纯力矩并在三个运动平面上旋转试样。载荷传感器和光学运动跟踪系统控制施加的载荷，并测量运动范围（ROM）和中立区（NZ）。作为概念验证，在实际实验条件下对新机器进行了验证，并将其与使用新鲜牛尾椎间盘 CY34（n = 10）验证过的现有试验机进行了比较：结果：新型脊柱测试仪通过滞后曲线测量出了合理的 ROM 和 NZ，两台测试仪的 ROM 形成了较高的决定系数 R 2 = 0.986。不过，新试验机的 ROM 结果更高，这可能是因为空气轴承的摩擦力更小，允许更多的平移运动：现在，TO GO脊柱测试仪为现场柔韧性测试提供了新的机会，并通过限制在宏观、生物力学、生物化学和组织学层面获得脊柱单元全面特征所需的实验动物数量，从而为 3R 原则做出了贡献。
{"title":"A novel spine tester TO GO","authors":"Jan Ulrich Jansen, Laura Zengerle, Marcel Steiner, Vincenza Sciortino, Marianna Tryfonidou, Hans-Joachim Wilke","doi":"10.1002/jsp2.70002","DOIUrl":"10.1002/jsp2.70002","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Often after large animal experiments in spinal research, the question arises—histology or biomechanics? While biomechanics are essential for informed decisions on the functionality of the therapy being studied, scientists often choose histological analysis alone. For biomechanical testing, for example, flexibility, specimens must be shipped to institutions with special testing equipment, as spine testers are complex and immobile. The specimens must usually be shipped frozen, and, thus, biological and histological investigations are not possible anymore. To allow both biomechanical and biological investigations with the same specimen and, thus, to reduce the number of required animals, the aim of the study was to develop a spine tester that can be shipped worldwide to test on-site.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The “Spine Tester TO GO” was designed consisting of a frame with three motors that initiate pure moments and rotate the specimen in three motion planes. A load cell and an optical motion tracking system controlled the applied loads and measured range of motion (ROM) and neutral zone (NZ). As a proof of concept, the new machine was validated and compared under real experimental conditions with an existing testing machine already validated employing fresh bovine tail discs CY34 (<i>n</i> = 10).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The new spine tester measured reasonable ROM and NZ from hysteresis curves, and the ROM of the two testing machines formed a high coefficient of determination <i>R</i><sup>2</sup> = 0.986. However, higher ROM results of the new testing machine might be explained by the lower friction of the air bearings, which allowed more translational motion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The spine tester TO GO now opens up new opportunities for on-site flexibility tests and contributes hereby to the 3R principle by limiting the number of experimental animals needed to obtain full characterization of spine units at the macroscopic, biomechanical, biochemical, and histological level.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Daqian Zhou, Tao Liu, Yongliang Mei, Jiale Lv, Kang Cheng, Weiye Cai, Silong Gao, Daru Guo, Xianping Xie, Zongchao Liu
Background
Intervertebral disc degeneration (IVDD) is an age-related orthopedic degenerative disease characterized by recurrent episodes of lower back pain, the pathogenesis of which is not fully understood. This study aimed to identify key biomarkers of IVDD and its causes.
Methods
We acquired three gene expression profiles from the Gene Expression Omnibus (GEO) database, GSE56081, GSE124272, and GSE153761, and used limma fast differential analysis to identify differentially expressed genes (DEGs) between normal and IVDD samples after removing batch effects. We applied weighted gene co-expression network (WGCNA) to identify the key modular genes in GSE124272 and intersected these with DEGs. Next, A protein–protein interaction network (PPI) was constructed, and Cytoscape was used to identify the Top 10 hub genes. Functional enrichment analyses were performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Three key genes were validated using Western Blot (WB) and qRT-PCR. Additionally, we predicted miRNAs involved in hub gene co-regulation and analyzed miRNA microarray data from GSE116726 to identify four differentially expressed miRNAs.
Results
We identified 10 hub genes using bioinformatics analysis, gene function enrichment analysis revealed that they were primarily enriched in pathways, such as the TNF signaling pathway. We chose JUNB, SOCS3, and CEBPB as hub genes and used WB and qRT-PCR to confirm their expression. All three genes were overexpressed in the IVDD model group compared to the control group. Furthermore, we identified four miRNAs involved in the co-regulation of the hub genes using miRNet prediction: mir-191-5p, mir-20a-5p, mir-155-5p, and mir-124-3p. Using limma difference analysis, we discovered that mir-191-5p, mir-20a-5p, and mir-155-5p were all down-regulated and expressed in IVDD samples, but mir-124-3p showed no significant change.
Conclusion
JUNB, SOCS3, and CEBPB were identified as key genes in IVDD, regulated by specific miRNAs, providing potential biomarkers for early diagnosis and therapeutic targets.
{"title":"Identifying critical modules and biomarkers of intervertebral disc degeneration by using weighted gene co-expression network","authors":"Daqian Zhou, Tao Liu, Yongliang Mei, Jiale Lv, Kang Cheng, Weiye Cai, Silong Gao, Daru Guo, Xianping Xie, Zongchao Liu","doi":"10.1002/jsp2.70004","DOIUrl":"https://doi.org/10.1002/jsp2.70004","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intervertebral disc degeneration (IVDD) is an age-related orthopedic degenerative disease characterized by recurrent episodes of lower back pain, the pathogenesis of which is not fully understood. This study aimed to identify key biomarkers of IVDD and its causes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We acquired three gene expression profiles from the Gene Expression Omnibus (GEO) database, GSE56081, GSE124272, and GSE153761, and used limma fast differential analysis to identify differentially expressed genes (DEGs) between normal and IVDD samples after removing batch effects. We applied weighted gene co-expression network (WGCNA) to identify the key modular genes in GSE124272 and intersected these with DEGs. Next, A protein–protein interaction network (PPI) was constructed, and Cytoscape was used to identify the Top 10 hub genes. Functional enrichment analyses were performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Three key genes were validated using Western Blot (WB) and qRT-PCR. Additionally, we predicted miRNAs involved in hub gene co-regulation and analyzed miRNA microarray data from GSE116726 to identify four differentially expressed miRNAs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 10 hub genes using bioinformatics analysis, gene function enrichment analysis revealed that they were primarily enriched in pathways, such as the TNF signaling pathway. We chose JUNB, SOCS3, and CEBPB as hub genes and used WB and qRT-PCR to confirm their expression. All three genes were overexpressed in the IVDD model group compared to the control group. Furthermore, we identified four miRNAs involved in the co-regulation of the hub genes using miRNet prediction: mir-191-5p, mir-20a-5p, mir-155-5p, and mir-124-3p. Using limma difference analysis, we discovered that mir-191-5p, mir-20a-5p, and mir-155-5p were all down-regulated and expressed in IVDD samples, but mir-124-3p showed no significant change.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>JUNB, SOCS3, and CEBPB were identified as key genes in IVDD, regulated by specific miRNAs, providing potential biomarkers for early diagnosis and therapeutic targets.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Khaled Aboushaala, Ana V. Chee, Darbaz Adnan, Sheila J. Toro, Harmanjeet Singh, Andrew Savoia, Ekamjeet S. Dhillon, Catherine Yuh, Jake Dourdourekas, Ishani K. Patel, Rajko Vucicevic, Alejandro A. Espinoza-Orias, John T. Martin, Chundo Oh, Ali Keshavarzian, Hanne B. Albert, Jaro Karppinen, Mehmet Kocak, Arnold Y. L. Wong, Edward J. Goldberg, Frank M. Phillips, Matthew W. Colman, Frances M. K. Williams, Jeffrey A. Borgia, Ankur Naqib, Stefan J. Green, Christopher B. Forsyth, Howard S. An, Dino Samartzis
Background
Lumbar degenerative spondylolisthesis (LDS), characterized as degeneration of the intervertebral disc and structural changes of the facet joints, is a condition with varying degrees of instability that may lead to pain, canal stenosis, and subsequent surgical intervention. However, the etiology of LDS remains inconclusive. Gut microbiome dysbiosis may stimulate systemic inflammation in various disorders. However, the role of such dysbiosis upon spine health remains under-studied. The current study assessed the association of gut microbiome dysbiosis in symptomatic patients with or without LDS.
Methods
A cross-sectional analysis within the framework of a prospective study was performed. DNA was extracted from fecal samples collected from adult symptomatic patients with (n = 21) and without LDS (n = 12). Alpha and beta diversity assessed differences in fecal microbial community between groups. Taxon-by-taxon analysis identified microbial features with differential relative abundance between groups. Subject demographics and imaging parameters were also assessed.
Results
There was no significant group differences in age, sex, race, body mass index, smoking/alcohol history, pain profiles, spinopelvic alignment, and Modic changes (p >0.05). LDS subjects had significantly higher disc degeneration severity (p = 0.018) and alpha diversity levels compared to non-LDS subjects (p = 0.002–0.003). Significant differences in gut microbial community structure were observed between groups (p = 0.046). Subjects with LDS exhibited distinct differences at the phylum level, with a significantly higher Firmicutes to Bacteroidota ratio compared to non-LDS (p = 0.003). Differential relative abundance analysis identified six taxa with significant differences between the two groups, with LDS demonstrating an increase in putative pro-inflammatory bacteria (Dialister, CAG-352) and a decrease in anti-inflammatory bacteria (Slackia, Escherichia-Shigella).
Conclusion
This study is the first to report a significant association of gut microbiome dysbiosis and LDS in symptomatic patients, noting pro-inflammatory bacterial taxa. This work provides a foundation for future studies addressing the role of the gut microbiome in association with spine health and disease.
{"title":"Gut microbiome dysbiosis is associated with lumbar degenerative spondylolisthesis in symptomatic patients","authors":"Khaled Aboushaala, Ana V. Chee, Darbaz Adnan, Sheila J. Toro, Harmanjeet Singh, Andrew Savoia, Ekamjeet S. Dhillon, Catherine Yuh, Jake Dourdourekas, Ishani K. Patel, Rajko Vucicevic, Alejandro A. Espinoza-Orias, John T. Martin, Chundo Oh, Ali Keshavarzian, Hanne B. Albert, Jaro Karppinen, Mehmet Kocak, Arnold Y. L. Wong, Edward J. Goldberg, Frank M. Phillips, Matthew W. Colman, Frances M. K. Williams, Jeffrey A. Borgia, Ankur Naqib, Stefan J. Green, Christopher B. Forsyth, Howard S. An, Dino Samartzis","doi":"10.1002/jsp2.70005","DOIUrl":"https://doi.org/10.1002/jsp2.70005","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lumbar degenerative spondylolisthesis (LDS), characterized as degeneration of the intervertebral disc and structural changes of the facet joints, is a condition with varying degrees of instability that may lead to pain, canal stenosis, and subsequent surgical intervention. However, the etiology of LDS remains inconclusive. Gut microbiome dysbiosis may stimulate systemic inflammation in various disorders. However, the role of such dysbiosis upon spine health remains under-studied. The current study assessed the association of gut microbiome dysbiosis in symptomatic patients with or without LDS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A cross-sectional analysis within the framework of a prospective study was performed. DNA was extracted from fecal samples collected from adult symptomatic patients with (<i>n</i> = 21) and without LDS (<i>n</i> = 12). Alpha and beta diversity assessed differences in fecal microbial community between groups. Taxon-by-taxon analysis identified microbial features with differential relative abundance between groups. Subject demographics and imaging parameters were also assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There was no significant group differences in age, sex, race, body mass index, smoking/alcohol history, pain profiles, spinopelvic alignment, and Modic changes (<i>p</i> >0.05). LDS subjects had significantly higher disc degeneration severity (<i>p</i> = 0.018) and alpha diversity levels compared to non-LDS subjects (<i>p</i> = 0.002–0.003). Significant differences in gut microbial community structure were observed between groups (<i>p</i> = 0.046). Subjects with LDS exhibited distinct differences at the phylum level, with a significantly higher Firmicutes to Bacteroidota ratio compared to non-LDS (<i>p</i> = 0.003). Differential relative abundance analysis identified six taxa with significant differences between the two groups, with LDS demonstrating an increase in putative pro-inflammatory bacteria (<i>Dialister, CAG-352</i>) and a decrease in anti-inflammatory bacteria (<i>Slackia</i>, <i>Escherichia-Shigella</i>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study is the first to report a significant association of gut microbiome dysbiosis and LDS in symptomatic patients, noting pro-inflammatory bacterial taxa. This work provides a foundation for future studies addressing the role of the gut microbiome in association with spine health and disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142429819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), worsened by chronic inflammatory processes associated with aging. Tumor necrosis factor alpha (Tnf-α) and its receptors, Tnf receptor type 1 (Tnfr1) and Tnf receptor type 2 (Tnfr2), are upregulated in IVDD. However, its pathologic mechanisms remain poorly defined.
Methods
To investigate the role of Tnfr in IVDD, we generated global Tnfr1/2 double knockout (KO) mice and age-matched control C57BL/6 male mice, and analyzed intervertebral disc (IVD)-related phenotypes of both genotypes under physiological conditions, aging, and lumbar spine instability (LSI) model through histological and immunofluorescence analyses and μCT imaging. Expression levels of key extracellular matrix (ECM) proteins in aged and LSI mice, especially markers of cell proliferation and apoptosis, were evaluated in aged (21-month-old) mice.
Results
At 4 months, KO and control mice showed no marked differences of IVDD-related parameters. However, at 21 months of age, the loss of Tnfr expression significantly alleviated IVDD-like phenotypes, including a significant increase in height of the nucleus pulposus (NPs) and reductions of endplates (EPs) porosity and histopathological scores, when compared to controls. Tnfr deficiency promoted anabolic metabolism of the ECM proteins and suppressed ECM catabolism. Tnfr loss largely inhibited hypertrophic differentiation, and, in the meantime, suppressed cell apoptosis and cellular senescence in the annulus fibrosis, NP, and EP tissues without affecting cell proliferation. Similar results were observed in the LSI model, where Tnfr deficiency significantly alleviated IVDD and enhanced ECM anabolic metabolism while suppressing catabolism.
Conclusion
The deletion of Tnfr mitigates age-related and LSI-induced IVDD, as evidenced by preserved IVD structure, and improved ECM integrity. These findings suggest a crucial role of Tnf-α/Tnfr signaling in IVDD pathogenesis in mice. Targeting this pathway may be a novel strategy for IVDD prevention and treatment.
{"title":"Inactivation of Tnf-α/Tnfr signaling attenuates progression of intervertebral disc degeneration in mice","authors":"Chu Tao, Sixiong Lin, Yujia Shi, Weiyuan Gong, Mingjue Chen, Jianglong Li, Peijun Zhang, Qing Yao, Dongyang Qian, Zemin Ling, Guozhi Xiao","doi":"10.1002/jsp2.70006","DOIUrl":"10.1002/jsp2.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), worsened by chronic inflammatory processes associated with aging. Tumor necrosis factor alpha (Tnf-α) and its receptors, Tnf receptor type 1 (Tnfr1) and Tnf receptor type 2 (Tnfr2), are upregulated in IVDD. However, its pathologic mechanisms remain poorly defined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To investigate the role of Tnfr in IVDD, we generated global Tnfr1/2 double knockout (KO) mice and age-matched control C57BL/6 male mice, and analyzed intervertebral disc (IVD)-related phenotypes of both genotypes under physiological conditions, aging, and lumbar spine instability (LSI) model through histological and immunofluorescence analyses and μCT imaging. Expression levels of key extracellular matrix (ECM) proteins in aged and LSI mice, especially markers of cell proliferation and apoptosis, were evaluated in aged (21-month-old) mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At 4 months, KO and control mice showed no marked differences of IVDD-related parameters. However, at 21 months of age, the loss of Tnfr expression significantly alleviated IVDD-like phenotypes, including a significant increase in height of the nucleus pulposus (NPs) and reductions of endplates (EPs) porosity and histopathological scores, when compared to controls. Tnfr deficiency promoted anabolic metabolism of the ECM proteins and suppressed ECM catabolism. Tnfr loss largely inhibited hypertrophic differentiation, and, in the meantime, suppressed cell apoptosis and cellular senescence in the annulus fibrosis, NP, and EP tissues without affecting cell proliferation. Similar results were observed in the LSI model, where Tnfr deficiency significantly alleviated IVDD and enhanced ECM anabolic metabolism while suppressing catabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The deletion of Tnfr mitigates age-related and LSI-induced IVDD, as evidenced by preserved IVD structure, and improved ECM integrity. These findings suggest a crucial role of Tnf-α/Tnfr signaling in IVDD pathogenesis in mice. Targeting this pathway may be a novel strategy for IVDD prevention and treatment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":"7 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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