scholarly journals Denosumab alleviates intervertebral disc degeneration adjacent to lumbar fusion by inhibiting endplate osteochondral remodeling and vertebral osteoporosis in ovariectomized rats

2021 ◽  
Vol 23 (1) ◽  
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 4 weeks after bilateral ovariectomy (OVX) surgery were given Dmab 4 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). Next, 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 L5/6 was evaluated by microcomputed tomography (μCT). The characteristic alterations of ASDD were identified via Safranin-O green staining. Osteoclasts were detected using tartrate-resistant acid phosphatase (TRAP) staining, and the biomechanical properties of vertebrae were evaluated. Aggrecan (Agg), metalloproteinase-13 (MMP-13), and 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. In addition, the expression of CD24 and Sox-9 was assessed by immunohistochemistry. 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 endplate porosity, and increasing vertebral biomechanical properties and BMD. TRAP staining results showed a significantly decreased number of active osteoclasts after Dmab treatment, especially in subchondral bone and cartilaginous endplates. Moreover, the protein and mRNA expression results in discs (IVDs) showed that Dmab not only inhibited matrix degradation by decreasing MMP-13 and ADAMTS-4 but also promoted matrix synthesis by increasing Agg. Dmab maintained the number of notochord cells by increasing CD24 but reducing Sox-9. Conclusions These results suggest that Dmab may be a novel therapeutic target for ASDD treatment.

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 Preventive and regenerative responses to 1- isothiocyanato-4-(methylsulfinyl) butane in annular puncture – induced model of rabbit intervertebral disc degeneration

2018 ◽  
Vol 7 (2) ◽  
pp. 1192-1205
Author(s):  
B. Ogunlade ◽  
S.A. Adelakun ◽  
O.P. Fidelis ◽  
F.M. Owolabi
Keyword(s):  
Intervertebral Disc ◽  
Oral Administration ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Histological Grade ◽  
Saline Group ◽  
Disc Height ◽  
X Rays ◽  
X Ray ◽  
Group I

This study aimed at investigating the preventive and rejuvenating capacity of 1-isothiocyanato-4-(methylsulfinyl) butanein annular punctured intervertebral disc degeneration in rabbit model.Twentyfive New Zealand white rabbits (1.5 to 3.0 kg each) underwent annular puncture.Group 1 received 50 mg/kg of phosphate-buffered saline orally for 8 weeks (non-punctured group); group 2 received 50 mg/kg phosphate-buffered salinesolution immediately after puncture for 8 weeks (model saline group I); group 3 received 50 mg/kg phosphate-buffered salinesolution after 8 weeks of puncture for another 8 weeks (model saline group II); group 4 received the oral  administration of 450 mg/kg of 1-isothiocyanato-4- (methylsulfinyl) Butane solution immediately after puncture for 8 weeks; group 5 received the oral administration of 450 mg/kg of 1-isothiocyanato-4-(methylsulfinyl) Butane solution after 8 weeks of puncture for another 8 weeks.Serial X-rays were performed at 0, 8 and 16weeks for the disc height. Upon sacrifice, the whole spinal column and discs were extracted and analyzed for various histological staining techniques (H&E and HVG), biochemical and immunohistochemical analysis. There wasdecreased in disc height in the X- ray and was significantly prevented and regenerated after the administration of 1-isothiocyanato-4-(methylsulfinyl) Butane solution. The histological grade, collagen type 1 and 2, aggrecan, and matrix metalloprotease-13 mRNA expression and histological analysiswere definitive in the degeneration processes thereby affirming the X-ray data. This study therefore ascertain that 1-isothiocyanato-4-(methylsulfinyl) Butane had anabolic effects on degenerated disc and could provide valuable information for consideration in clinical trials.Keywords: Low back pain, intervertebral disc degeneration, 1-isothiocyanato-4-(methylsulfinyl) Butane,histology.

scholarly journals Outcomes in cases of lumbar degenerative spondylolisthesis more than 5 years after treatment with minimally invasive decompression: examination of pre- and postoperative slippage, intervertebral disc changes, and clinical results

2016 ◽  
Vol 24 (3) ◽  
pp. 367-374 ◽  
Author(s):  
Gen Mori ◽  
Yasuo Mikami ◽  
Yuji Arai ◽  
Takumi Ikeda ◽  
Masateru Nagae ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Degenerative Spondylolisthesis ◽  
Clinical Results ◽  
Natural Course ◽  
Disc Height ◽  
Minimally Invasive Decompression

OBJECT There are reports that fusion is the standard treatment of choice for cases of lumbar degenerative spondylolisthesis (LDS) associated with lumbar spinal canal stenosis with a large degree of slippage. The reasons why, however, have not been clarified. On the other hand, it is known that the progress of slippage decreases and restabilization occurs over the natural course of LDS. Therefore, if minimally invasive decompression could be performed, there would be little possibility of it influencing the natural course of LDS, so it would not be necessary to include preoperative percentage slip in the criteria for the selection of fusion. This study examined the course of LDS cases more than 5 years after treatment with minimally invasive decompression to determine whether pre- and postoperative slippage and disc changes influence the clinical results. METHODS A total of 51 intervertebral segments in 51 cases with the chief complaint of radicular or cauda equina symptoms due to lumbar spinal canal stenosis were examined after prospective treatment with minimally invasive decompression for LDS. The mean age of the patients at the time of surgery was 66.7 years and the mean follow-up period was 7 years 4 months. Minimally invasive decompression was performed regardless of the degree of low-back pain or percentage slip. The outcome variables were clinical results and changes in imaging findings. RESULTS Over the follow-up period, postoperative percentage slip increased and disc height decreased, but the Japanese Orthopaedic Association score improved. Regardless of the preoperative percentage slip, disc height, or degree of intervertebral disc degeneration or segmental instability, the clinical results were favorable. In the high preoperative percentage slip group, low disc height group, and progressive disc degeneration group, there was little postoperative progress of slippage. In the group with a postoperative slippage increase of more than 5%, slippage increased significantly at postoperative year 2, but no significant difference was observed at the final follow-up. CONCLUSIONS When minimally invasive decompression was performed to treat LDS, the postoperative change in slippage was no different from that during the natural course. Furthermore, regardless of the degree of preoperative slippage or intervertebral disc degeneration, the clinical results were favorable. Also, the higher the preoperative percentage slip and the more that disc degeneration progressed, the more the progress of postoperative slippage decreased. Because the postoperative progress of slippage decreased, it is believed that even after minimally invasive decompression, restabilization occurs as it would during the natural course. If minimally invasive decompression can be performed to treat LDS, it is believed that preoperative percentage slip and intervertebral disc degeneration do not have to be included in the appropriateness criteria for fusion.

Recovery of Intervertebral Disc Degeneration Post Enzymatic Treatment is Mediated by Matrix Metalloproteinases

2011 ◽  
Author(s):  
Nadeen Chahine ◽  
Nate Stetson ◽  
Neena Rajan ◽  
Daniel Grande ◽  
Mitchell Levine
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Enzymatic Degradation ◽  
Intervertebral Disc Degeneration ◽  
Biomechanical Properties ◽  
Enzymatic Treatment ◽  
Disc Injury ◽  
Herniated Discs ◽  
Dose Dependent

Enzymatic degradation of the intervertebral disc (IVD) with chondroitinase ABC (ChABC) reduces proteoglycan content of the IVD, thus simulating the GAG loss seen clinically in patients suffering from disc degeneration. This approach has been employed in models of disc injury in rats, rabbits and goats when administered over a large range of dosages [1–3]. Moreover, ChABC has also been used to induce repair of herniated discs in rabbits via chemonucleolysis [4, 5]. Despite the effectiveness of ChABC treatment to reduce the GAG content of the IVD, several recent studies including our own, have shown that this GAG loss is reversible at extended time points post enzymatic treatment [2,6,7]. The goal of the current study is to examine the dose dependent response of IVDs to degradation by ChABC in vivo. We hypothesize that administration of ChABC will result in dose dependent GAG loss and reduced mechanical properties. We administered ChABC at 0.1 U/ml, 1.0 U/ml and 10 U/ml and examined the changes in biomechanical properties, biochemical content, and gene expression in order to examine the biophysical and molecular mechanism by which GAG loss occurs in this model.

scholarly journals Platelet-Derived Biomaterials Exert Chondroprotective and Chondroregenerative Effects on Diabetes Mellitus-Induced Intervertebral Disc Degeneration

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1054
Author(s):  
Wen-Cheng Lo ◽  
Chun-Chao Chang ◽  
Chun-Hao Chan ◽  
Abhinay Kumar Singh ◽  
Yue-Hua Deng ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Growth Factor ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Transforming Growth Factor ◽  
Disc Height ◽  
Therapeutic Effects

Complications of diabetes mellitus (DM) range from acute to chronic conditions, leading to multiorgan disorders such as nephropathy, retinopathy, and neuropathy. However, little is known about the influence of DM on intervertebral disc degeneration (IVDD). Moreover, traditional surgical outcomes in DM patients have been found poor, and to date, no definitive alternative treatment exists for DM-induced IVDD. Recently, among various novel approaches in regenerative medicine, the concentrated platelet-derived biomaterials (PDB), which is comprised of transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF), etc., have been reported as safe, biocompatible, and efficacious alternatives for various disorders. Therefore, we initially investigated the correlations between DM and IVDD, through establishing in vitro and in vivo DM models, and further evaluated the therapeutic effects of PDB in this comorbid pathology. In vitro model was established by culturing immortalized human nucleus pulposus cells (ihNPs) in high-glucose medium, whereas in vivo DM model was developed by administering streptozotocin, nicotinamide and high-fat diet to the mice. Our results revealed that DM deteriorates both ihNPs and IVD tissues, by elevating reactive oxygen species (ROS)-induced oxidative stress, inhibiting chondrogenic markers and disc height. Contrarily, PDB ameliorated IVDD by restoring cellular growth, chondrogenic markers and disc height, possibly through suppressing ROS levels. These data imply that PDB may serve as a potential chondroprotective and chondroregenerative candidate for DM-induced IVDD.

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