Molecular changes to tendons after collagenase-induced acute tendon injury in a senescence-accelerated mouse model

doi:10.1186/s12891-019-2488-1

. 2019 Mar 21;20(1):120.

doi: 10.1186/s12891-019-2488-1.

Molecular changes to tendons after collagenase-induced acute tendon injury in a senescence-accelerated mouse model

Yasuhiro Ueda¹, Atsuyuki Inui¹, Yutaka Mifune², Fumiaki Takase¹, Takeshi Kataoka¹, Takashi Kurosawa¹, Kohei Yamaura¹, Takeshi Kokubu¹, Ryosuke Kuroda¹

Affiliations

¹ Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, chuo-ku, Kobe, 650-0017, Japan.
² Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, chuo-ku, Kobe, 650-0017, Japan. m-ship@kf7.so-net.ne.jp.

PMID: 30902076
PMCID: PMC6429773
DOI: 10.1186/s12891-019-2488-1

Molecular changes to tendons after collagenase-induced acute tendon injury in a senescence-accelerated mouse model

Yasuhiro Ueda et al. BMC Musculoskelet Disord. 2019.

. 2019 Mar 21;20(1):120.

doi: 10.1186/s12891-019-2488-1.

Authors

Yasuhiro Ueda¹, Atsuyuki Inui¹, Yutaka Mifune², Fumiaki Takase¹, Takeshi Kataoka¹, Takashi Kurosawa¹, Kohei Yamaura¹, Takeshi Kokubu¹, Ryosuke Kuroda¹

Affiliations

¹ Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, chuo-ku, Kobe, 650-0017, Japan.
² Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, chuo-ku, Kobe, 650-0017, Japan. m-ship@kf7.so-net.ne.jp.

PMID: 30902076
PMCID: PMC6429773
DOI: 10.1186/s12891-019-2488-1

Abstract

Background: Aging impairs tendon healing and is a potential risk factor for chronic tendinitis. During normal aging, tendons undergo structural and biomechanical degenerative changes, accompanied by a reduction in the number of tenocytes and changes to their properties. However, molecular changes in aged tendons under inflammatory conditions are not well understood. The present study analyzed the molecular changes in collagenase induced acute tendon injury using a senescence-accelerated mouse (SAM) model.

Methods: SAMP6 mice were used as an aging animal model and SAMR1 mice were used as a control to represent a senescence-resistant inbred strain. All the mice used in the study were 40 weeks old. Collagenase I from Clostridium histolyticum (20 μL) was injected percutaneously to the tendon-bone junction of the Achilles tendon. Two weeks after treatment, the Achilles tendons were harvested and stained using Picrosirius Red to determine collagen expression. Real-time PCR was performed to analyze gene expression of IL-6, tenomodulin, type I and type II collagen, MMP-9, TIMP-1, and TIMP-2.

Results: Collagenase injection resulted in significantly higher gene expression of IL-6 but significantly lower tenomodulin expression compared with the control in SAMP6 and SAMR1 mice. In SAMP6 mice, gene expression of type III collagen and MMP-9 was significantly higher in the collagenase-injected group compared with the control group. SAMP6 mice also showed lower expression of type I collagen, TIMP-1, and TIMP-2 in the collagenase-injected group compared with the control group. Picrosirius Red staining showed the highest expression of type III collagen in the collagenase-injected SAMP6 group compared with the other groups.

Conclusions: The collagenase-injected SAMP6 group showed higher expression of IL-6, MMP-9, and type III collagen and lower expression of type I collagen, TIMP-1, and TIMP-2, which are known to suppress metalloproteinases. The results indicate that aging may lead to dysfunction of the tendon healing process after acute tendon injury.

Keywords: Acute tendon injury; Aging; Tendon degeneration.

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Conflict of interest statement

Ethics approval and consent to participate

Our IRB (Institutional Animal Care and Use Committee At kusunoki and Myodani Campus Kobe University) provided the approval for our study and the approval informations are follows. (Permission Number: P140610-R1). All animal procedures were performed under the approval and guidance of our IRB.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
mRNA expressions in the Achilles tendons of SAMR1 and SAMP6. a IL-6 is a marker for inflammation, b, c type I and type III collagen are markers for degeneration, and d, e, f, g tenomodulin, MMP-9, TIMP-1, and TIMP-2 are markers for tendon remodeling. (*p < 0.05). a. mRNA expression of IL-6. b. mRNA expression of type I collagen. c. mRNA expression of type III collagen. d. mRNA expression of tenomodulin. e. mRNA expression of MMP-9. f. mRNA expression of TIMP-1. g. mRNA expression of TIMP-2

**Fig. 2**
Collagen arrangement in the Achilles tendon stained using Picrosirius Red. Yellow represent type I collagen and green represents type III collagen

**Fig. 3**
Expression of type I collagen in the Achilles tendon detected by Picrosirius Red staining. Expression of type I collagen was semiquantitatively analyzed by the chromaticity of yellow in Fig. 2. (*p < 0.05)

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References

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1. Robinson PM, Wilson J, Dalal S, Parker RA, Norburn P, Roy BR. Rotator cuff repair in patients over 70 years of age: early outcomes and risk factors associated with re-tear. Bone Joint J. 2013;95-b(2):199–205. doi: 10.1302/0301-620X.95B2.30246. - DOI - PubMed
1. Matough FA, Budin SB, Hamid ZA, Alwahaibi N, Mohamed J. The role of oxidative stress and antioxidants in diabetic complications. Sultan Qaboos Univ Med J. 2012;12(1):5–18. doi: 10.12816/0003082. - DOI - PMC - PubMed
1. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–839. doi: 10.1161/01.RES.0000070112.80711.3D. - DOI - PubMed
1. Yu TY, Pang JH, Wu KP, Chen MJ, Chen CH, Tsai WC. Aging is associated with increased activities of matrix metalloproteinase-2 and -9 in tenocytes. BMC Musculoskelet Disord. 2013;14:2. doi: 10.1186/1471-2474-14-2. - DOI - PMC - PubMed

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[1] Steinbacher P, Tauber M, Kogler S, Stoiber W, Resch H, Sanger AM. Effects of rotator cuff ruptures on the cellular and intracellular composition of the human supraspinatus muscle. Tissue Cell. 2010;42(1):37–41. doi: 10.1016/j.tice.2009.07.001. - DOI - PubMed

[2] Steinbacher P, Tauber M, Kogler S, Stoiber W, Resch H, Sanger AM. Effects of rotator cuff ruptures on the cellular and intracellular composition of the human supraspinatus muscle. Tissue Cell. 2010;42(1):37–41. doi: 10.1016/j.tice.2009.07.001. - DOI - PubMed

[3] Robinson PM, Wilson J, Dalal S, Parker RA, Norburn P, Roy BR. Rotator cuff repair in patients over 70 years of age: early outcomes and risk factors associated with re-tear. Bone Joint J. 2013;95-b(2):199–205. doi: 10.1302/0301-620X.95B2.30246. - DOI - PubMed

[4] Robinson PM, Wilson J, Dalal S, Parker RA, Norburn P, Roy BR. Rotator cuff repair in patients over 70 years of age: early outcomes and risk factors associated with re-tear. Bone Joint J. 2013;95-b(2):199–205. doi: 10.1302/0301-620X.95B2.30246. - DOI - PubMed

[5] Matough FA, Budin SB, Hamid ZA, Alwahaibi N, Mohamed J. The role of oxidative stress and antioxidants in diabetic complications. Sultan Qaboos Univ Med J. 2012;12(1):5–18. doi: 10.12816/0003082. - DOI - PMC - PubMed

[6] Matough FA, Budin SB, Hamid ZA, Alwahaibi N, Mohamed J. The role of oxidative stress and antioxidants in diabetic complications. Sultan Qaboos Univ Med J. 2012;12(1):5–18. doi: 10.12816/0003082. - DOI - PMC - PubMed

[7] Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–839. doi: 10.1161/01.RES.0000070112.80711.3D. - DOI - PubMed

[8] Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92(8):827–839. doi: 10.1161/01.RES.0000070112.80711.3D. - DOI - PubMed

[9] Yu TY, Pang JH, Wu KP, Chen MJ, Chen CH, Tsai WC. Aging is associated with increased activities of matrix metalloproteinase-2 and -9 in tenocytes. BMC Musculoskelet Disord. 2013;14:2. doi: 10.1186/1471-2474-14-2. - DOI - PMC - PubMed

[10] Yu TY, Pang JH, Wu KP, Chen MJ, Chen CH, Tsai WC. Aging is associated with increased activities of matrix metalloproteinase-2 and -9 in tenocytes. BMC Musculoskelet Disord. 2013;14:2. doi: 10.1186/1471-2474-14-2. - DOI - PMC - PubMed

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