Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease

Khoi Than, Shayan U. Rahman, Lin Wang, Adam Khan, Kwaku A. Kyere, Tracey T. Than, Yoshinari Miyata, Yoon Shin Park, Frank La Marca, Hyungjin M. Kim, Huina Zhang, Paul Park, Chia Ying Lin

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background context A large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein 2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to upregulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD. Purpose The purpose of the present study was to develop a novel conservative treatment for DDD and related discogenic back pain. Study design/setting The setting of this study is the laboratory investigation. Methods Disc injury was induced in 272 rats via 21-ga needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the magnetic resonance imaging (MRI) index (number of pixels multiplied by the corresponding image densities) was determined. Histologically, disc spaces were read by three blinded scorers using a previously described histologic grading scale. Genetically, nuclei pulposi were harvested, and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression. Results Radiologically, discs treated with 5 mg/mL of simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks after treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated improved grades compared with discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. Conclusions Degenerate discs treated with 5 mg/mL of simvastatin in a hydrogel carrier demonstrated radiographic and histologic features resembling normal noninjured IVDs. In addition, the gene expression of aggrecan and collagen type II (important constituents of the IVD extracellular matrix) was upregulated in treated discs. Injection of simvastatin into degenerate IVDs may result in retardation of disc degeneration and represents a promising investigational therapy for conservative treatment of DDD.

Original languageEnglish (US)
Pages (from-to)1017-1028
Number of pages12
JournalSpine Journal
Volume14
Issue number6
DOIs
StatePublished - Jun 1 2014
Externally publishedYes

Fingerprint

Simvastatin
Regeneration
Hydrogel
Injections
Aggrecans
Bone Morphogenetic Protein 2
Collagen Type II
Intervertebral Disc Degeneration
Intervertebral Disc
Back Pain
Gene Expression
Magnetic Resonance Imaging
Chondrogenesis
Investigational Therapies
Punctures
Needles
Extracellular Matrix
Up-Regulation
Outcome Assessment (Health Care)
Polymerase Chain Reaction

Keywords

  • Back pain
  • BMP-2
  • Degenerative disc disease
  • Discogenic back pain
  • Rodent model
  • Simvastatin

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease. / Than, Khoi; Rahman, Shayan U.; Wang, Lin; Khan, Adam; Kyere, Kwaku A.; Than, Tracey T.; Miyata, Yoshinari; Park, Yoon Shin; La Marca, Frank; Kim, Hyungjin M.; Zhang, Huina; Park, Paul; Lin, Chia Ying.

In: Spine Journal, Vol. 14, No. 6, 01.06.2014, p. 1017-1028.

Research output: Contribution to journalArticle

Than, K, Rahman, SU, Wang, L, Khan, A, Kyere, KA, Than, TT, Miyata, Y, Park, YS, La Marca, F, Kim, HM, Zhang, H, Park, P & Lin, CY 2014, 'Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease', Spine Journal, vol. 14, no. 6, pp. 1017-1028. https://doi.org/10.1016/j.spinee.2013.11.034
Than, Khoi ; Rahman, Shayan U. ; Wang, Lin ; Khan, Adam ; Kyere, Kwaku A. ; Than, Tracey T. ; Miyata, Yoshinari ; Park, Yoon Shin ; La Marca, Frank ; Kim, Hyungjin M. ; Zhang, Huina ; Park, Paul ; Lin, Chia Ying. / Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease. In: Spine Journal. 2014 ; Vol. 14, No. 6. pp. 1017-1028.
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abstract = "Background context A large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein 2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to upregulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD. Purpose The purpose of the present study was to develop a novel conservative treatment for DDD and related discogenic back pain. Study design/setting The setting of this study is the laboratory investigation. Methods Disc injury was induced in 272 rats via 21-ga needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the magnetic resonance imaging (MRI) index (number of pixels multiplied by the corresponding image densities) was determined. Histologically, disc spaces were read by three blinded scorers using a previously described histologic grading scale. Genetically, nuclei pulposi were harvested, and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression. Results Radiologically, discs treated with 5 mg/mL of simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks after treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated improved grades compared with discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. Conclusions Degenerate discs treated with 5 mg/mL of simvastatin in a hydrogel carrier demonstrated radiographic and histologic features resembling normal noninjured IVDs. In addition, the gene expression of aggrecan and collagen type II (important constituents of the IVD extracellular matrix) was upregulated in treated discs. Injection of simvastatin into degenerate IVDs may result in retardation of disc degeneration and represents a promising investigational therapy for conservative treatment of DDD.",
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author = "Khoi Than and Rahman, {Shayan U.} and Lin Wang and Adam Khan and Kyere, {Kwaku A.} and Than, {Tracey T.} and Yoshinari Miyata and Park, {Yoon Shin} and {La Marca}, Frank and Kim, {Hyungjin M.} and Huina Zhang and Paul Park and Lin, {Chia Ying}",
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AU - Than, Khoi

AU - Rahman, Shayan U.

AU - Wang, Lin

AU - Khan, Adam

AU - Kyere, Kwaku A.

AU - Than, Tracey T.

AU - Miyata, Yoshinari

AU - Park, Yoon Shin

AU - La Marca, Frank

AU - Kim, Hyungjin M.

AU - Zhang, Huina

AU - Park, Paul

AU - Lin, Chia Ying

PY - 2014/6/1

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N2 - Background context A large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein 2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to upregulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD. Purpose The purpose of the present study was to develop a novel conservative treatment for DDD and related discogenic back pain. Study design/setting The setting of this study is the laboratory investigation. Methods Disc injury was induced in 272 rats via 21-ga needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the magnetic resonance imaging (MRI) index (number of pixels multiplied by the corresponding image densities) was determined. Histologically, disc spaces were read by three blinded scorers using a previously described histologic grading scale. Genetically, nuclei pulposi were harvested, and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression. Results Radiologically, discs treated with 5 mg/mL of simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks after treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated improved grades compared with discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. Conclusions Degenerate discs treated with 5 mg/mL of simvastatin in a hydrogel carrier demonstrated radiographic and histologic features resembling normal noninjured IVDs. In addition, the gene expression of aggrecan and collagen type II (important constituents of the IVD extracellular matrix) was upregulated in treated discs. Injection of simvastatin into degenerate IVDs may result in retardation of disc degeneration and represents a promising investigational therapy for conservative treatment of DDD.

AB - Background context A large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein 2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to upregulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD. Purpose The purpose of the present study was to develop a novel conservative treatment for DDD and related discogenic back pain. Study design/setting The setting of this study is the laboratory investigation. Methods Disc injury was induced in 272 rats via 21-ga needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the magnetic resonance imaging (MRI) index (number of pixels multiplied by the corresponding image densities) was determined. Histologically, disc spaces were read by three blinded scorers using a previously described histologic grading scale. Genetically, nuclei pulposi were harvested, and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression. Results Radiologically, discs treated with 5 mg/mL of simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks after treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated improved grades compared with discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. Conclusions Degenerate discs treated with 5 mg/mL of simvastatin in a hydrogel carrier demonstrated radiographic and histologic features resembling normal noninjured IVDs. In addition, the gene expression of aggrecan and collagen type II (important constituents of the IVD extracellular matrix) was upregulated in treated discs. Injection of simvastatin into degenerate IVDs may result in retardation of disc degeneration and represents a promising investigational therapy for conservative treatment of DDD.

KW - Back pain

KW - BMP-2

KW - Degenerative disc disease

KW - Discogenic back pain

KW - Rodent model

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