The online version of this article (doi:10.1186/ar3454) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
HEG, in collaboration with ENH, conceived and planned the study. GLH performed microarray analyses, while JAI and NZ performed histology and immunohistochemistry. HEG wrote the manuscript and performed statistical analyses with HJN. Co-authors agreed with the finalized submission. All authors read and approved the final manuscript.
Cathepsin K is a recently discovered cysteine protease which cleaves the triple helical domains of type I to II collagen. It has been shown to be up-regulated in synovial tissue from osteoarthritic and rheumatoid patients, and is a component in normal and nonarthritic cartilage, where it increases with aging. Studies on heart valve development have recently shown that receptor activator of nuclear factor-κB ligand (RANKL) acts during valve remodeling to promote cathepsin K expression. Since extracellular matrix remodeling is a critical component of disc structure and biomechanical function, we hypothesized that cathepsin K and RANKL may be present in the human intervertebral disc.
Studies were performed following approval of the authors' Human Subjects Institutional Review Board. Six annulus specimens from healthier Thompson grade I to II discs, and 12 specimens from more degenerate grade III to IV discs were utilized in microarray analysis of RANKL and cathepsin K gene expression. Immunohistochemistry was also performed on 15 additional disc specimens to assess the presence of RANKL and cathepsin K.
Cathepsin K gene expression was significantly greater in more degenerated grade III to IV discs compared to healthier grade I to II discs (P = 0.001). RANKL was also identified with immunohistochemistry and molecular analyses. RANKL gene expression was also significantly greater in more degenerated discs compared to healthier ones (P = 0.0001). A significant linear positive correlation was identified between expression of cathepsin K and RANKL (r2 = 92.2; P < 0.0001).
Extracellular matrix remodeling is a key element of disc biology. Our use of an appropriate antibody and gene expression studies showed that cathepsin K is indeed present in the human intervertebral disc. Immunolocalization and molecular analyses also confirmed that RANKL is present in the human disc. Expression of RANKL was found to be significantly greater in more degenerated compared to healthier discs (P = 0.0001). Cathepsin K gene expression levels showed a positive, significant correlation with RANKL expression. Based on these data, we propose that cathepsin K plays a significant role in disc matrix remodeling and in matrix degradation in the proinflammatory cytokine-rich microenvironment of the degenerating disc.
Authors’ original file for figure 113075_2011_3205_MOESM1_ESM.tiff
Authors’ original file for figure 213075_2011_3205_MOESM2_ESM.tiff
Authors’ original file for figure 313075_2011_3205_MOESM3_ESM.tiff
Authors’ original file for figure 413075_2011_3205_MOESM4_ESM.tiff
Authors’ original file for figure 513075_2011_3205_MOESM5_ESM.tiff
Tezuka K, Tezuka Y, Maejima A, Sato T, Nemoto K, Kamioka H, Hakeda Y, Kamegawa M: Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J Biol Chem. 1994, 269: 1106-1109. PubMed
Hummell KM, Petrow PK, Franz JK, Muller-Ladner U, Aicher WK, Gay RE, Bromme D, Gay S: Cysteine proteinase cathepsin K mRNA is expressed in synovium of patients with rheumatoid arthritis and is detected at sites of synovial bone descruction. J Rheumatol. 1998, 25: 1887-1894.
Konttinen YT, Mandelin J, Li T-F, Salo J, Lassus J, Liljeström M, Hukkanen M, Tagai M, Virtanen I, Santavirta S: Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis. Arthritis Rheum. 2002, 46: 953-960. 10.1002/art.10185. CrossRefPubMed
Dejica VM, Mort JS, Laverty S, Percival MD, Antoniou J, Zukor DJ, Poole AR: Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Amer J Pathol. 2008, 173: 161-169. 10.2353/ajpath.2008.070494. CrossRef
Dombs MD, Yutzey KE: VEGF and RANKL regulation of NFATc1 in heart valve development. Circ Res. 2009, 105: 565-574. 10.1161/CIRCRESAHA.109.196469. CrossRef
Neidhart M, Baraliakos X, Seemayer C, Zelder D, Gay RE, Michel BA, Boehm H, Gay S, Braun J: Expression of cathepsin K and matrix metalloproteinase 1 indicate persistent osteodestructive activity in long-standing ankylosing spondylitis. Ann Rheum Dis. 2009, 68: 1334-1339. 10.1136/ard.2008.092494. CrossRefPubMed
Auuerbach JD, Johnnessen W, Borthakur A, Wheaton AJ, Dolinskas CA, Balderston RA, Reddy R, Elliott DM: In vivo quantification of human lumbar disc degeneration using T(1rho)-weighted magnetic resonance imaging. Eur Spine J. 2006, 15: S338-S344. 10.1007/s00586-006-0083-2. CrossRef
Millward-Sadler SJ, Costello PW, Freemont AJ, Hoyland JA: Regulation of catabolic gene expression in normal and degenerate human intervertebral disc cells: implications for the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther. 2009, 11: R65-10.1186/ar2693. PubMedCentralCrossRefPubMed
Gruber HE, Ingram JA, Hoelscher GL, Zinchenko N, Norton HJ, Hanley EN: Matrix metalloproetinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs. Arthritis Res Ther. 2009, 11: R184-10.1186/ar2876. PubMedCentralCrossRefPubMed
Shen B, Melrose J, Ghosh P, Taylor TKF: Induction of matrix metalloproteinase-2 and -3 activity in ovine nucleus pulposus cells grown in three-dimensional agarose gel culture by interleukin-1β: a potential pathway of disc degeneration. Eur Spine J. 2003, 12: 66-75. PubMed
Momohara S, Okamoto H, Komiya K, Ikari K, Tadkuchi M, Tomatsu T, Kamatani N: Matrix metalloproteinase 28/epilysin expression in cartilage from patients with rheumatoid arthritis and osteoarthritis: comment on the article by Kevorkian et al. Arthritis Rheum. 2004, 50: 4074-4080. 10.1002/art.20799. CrossRefPubMed
Singh K, Masuda K, Thonar EJMA, An HS, Cs-Szabo G: Age-related changes in the extracellular matrix of nucleus pulposus and anulus fibrosus of human intervertebral disc. Spine. 2008, 34: 10-16. CrossRef
Freemont AJ: The cellular pathobiology of the degenerate intervertebral disc and discogenic back pain. Rheumatology (Oxford). 2009, 48: 5-10. CrossRef
LeMaitre CL, Freemont AJ, Hoyland JA: The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther. 2005, 7: R732-R745. 10.1186/ar1732. CrossRef
LeMaitre CL, Hoyland JA, Freemont AJ: Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1ß and TNFa expression profile. Arthritis Res Ther. 2007, 9: R77-10.1186/ar2275. CrossRef
Hoyland JA, Le Maitre C, Freemont AJ: Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc. Rheumatol. 2008, 47: 809-814. 10.1093/rheumatology/ken056. CrossRef
Mackiewicz A, Salo J, Konttinen YT, Holm AK, Indayl A, Pajarinen J, Holm S: Receptor activator of nuclear factor kappa B ligand in an experimental intervertebral disc degeneration. Clin Exp Rheumatol. 2009, 27: 299-306. PubMed
Stroup GB, Lark MW, Veber DF, Bhattacharyya A, Blake S, Dare LC, Erhard KF, Hoffman SF, James IE, Marquis RW, Ru Y, Vasko-Moser JA, Tomaszet T, Gowen M: Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J Bone Mineral Res. 2001, 16: 1739-1746. 10.1359/jbmr.2001.16.10.1739. CrossRef
- Constitutive expression of cathepsin K in the human intervertebral disc: new insight into disc extracellular matrix remodeling via cathepsin K and receptor activator of nuclear factor-κB ligand
Helen E Gruber
Jane A Ingram
Gretchen L Hoelscher
H James Norton
Edward N Hanley Jr
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II