This mini-review aims to introduce the association between Secretory clusterin/apolipoprotein J (sCLU) and diverse musculoskeletal diseases. A comprehensive review of the literature was performed to identify basic science and clinical studies, which implied the therapeutic and prognostic role of sCLU in diverse musculoskeletal diseases. sCLU is a multifunctional glycoprotein that is ubiquitously expressed in various tissues and is implicated in many pathophysiological processes. Dysregulated expression of sCLU had been reported to be assocaited with proliferative or apoptotic molecular processes and inflammatory responses, which participated in many pathophysiological processes such as degenerative musculoskeletal diseases including ischemic osteonecrosis, osteoarthritis (OA) and degenerative cervical myelopathy (spinal cord injury), neoplastic musculoskeletal diseases, inflammatory and autoimmune musculoskeletal diseases including Rheumatoid arthritis (RA), joint damage induced by Brucella abortus, Sjogren's syndrome, idiopathic inflammatory myopathies, muscle glucose metabolism, insulin sensitivity and traumatic musculoskeletal diseases. Recent findings of sCLU in these musculoskeletal diseases provides insights on the therapeutic and prognostic role of sCLU in these musculoskeletal diseases. sCLU may serve as a promising therapeutic target for ischemic osteonecrosis, OA and spinal cord injury as well as a potential prognostic biomarker for OA and RA. Moreover, sCLU could act as a prognostic biomarker for osteosarcoma (OS) and a promising therapeutic target for OS resistance. Although many studies support the potential therapeutic and prognostic role of sCLU in some inflammatory and autoimmune-mediated musculoskeletal diseases, more future researches are needed to explore the molecular pathogenic mechanism mediated by sCLU implied in these musculoskeletal diseases.

Department of Joint Surgery Honghui Hospital Xi'an Jiaotong University Xi'an China

Zobrazit více v PubMed

Hogg SD, Embery G. The isolation and partial characterization of a sulphated glycoprotein from human whole saliva which aggregates strains of Streptococcus sanguis but not Streptococcus mutans. Arch Oral Biol. 1979;24:791–797. doi: 10.1016/0003-9969(79)90040-2. PubMed DOI

Blaschuk O, Burdzy K, Fritz IB. Purification and characterization of a cell-aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid. J Biol Chem. 1983;258:7714–7720. doi: 10.1016/S0021-9258(18)32238-5. PubMed DOI

Wilson MR, Easterbrook-Smith SB. Clusterin is a secreted mammalian chaperone. Trends Biochem Sci. 2000;25:95–98. doi: 10.1016/S0968-0004(99)01534-0. PubMed DOI

Rodriguez-Rivera C, Garcia MM, Molina-Alvarez M, Gonzalez-Martin C, Goicoechea C. Clusterin: Always protecting. Synthesis, function and potential issues. Biomed Pharmacother. 2021;134:111174. doi: 10.1016/j.biopha.2020.111174. PubMed DOI

Rohne P, Prochnow H, Koch-Brandt C. The CLU-files: disentanglement of a mystery. Biomol Concepts. 2016;7:1–15. doi: 10.1515/bmc-2015-0026. PubMed DOI

Klimaschewski L, Obermüller N, Witzgall R. Regulation of clusterin expression following spinal cord injury. Cell Tissue Res. 2001;306:209–216. doi: 10.1007/s004410100431. PubMed DOI

Fandridis E, Apergis G, Korres DS, Nikolopoulos K, Zoubos AB, Papassideri I, Trougakos IP. Increased expression levels of apolipoprotein J/clusterin during primary osteoarthritis. In Vivo. 2011;25:745–749. PubMed

Kropáčková T, Mann H, Růžičková O, Šléglová O, Vernerová L, Horváthová V, Tomčík M, Pavelka K, Vencovský J, Šenolt L. Clusterin serum levels are elevated in patients with early rheumatoid arthritis and predict disease activity and treatment response. Sci Rep. 2021;11:11525. doi: 10.1038/s41598-021-90973-2. PubMed DOI PMC

Huang H, Wang L, Li M, Wang X, Zhang L. Secreted clusterin (sCLU) regulates cell proliferation and chemosensitivity to cisplatin by modulating ERK1/2 signals in human osteosarcoma cells. World J Surg Oncol. 2014;12:255. doi: 10.1186/1477-7819-12-255. PubMed DOI PMC

Wang X, Yu Y, Zang L, Zhang P, Ma J, Chen D. Targeting Clusterin Induces Apoptosis, Reduces Growth Ability and Invasion and Mediates Sensitivity to Chemotherapy in Human Osteosarcoma Cells. Curr Pharm Biotechnol. 2020;21:131–139. doi: 10.2174/1389201020666190821151120. PubMed DOI

Devauchelle V, Essabbani A, De PG, Germain S, Tourneur L, Mistou S, Margottin-Goguet F, Anract P, Migaud H, Le ND, Lequerré T, Saraux A, Dougados M, Breban M, Fournier C, Chiocchia G. Characterization and functional consequences of underexpression of clusterin in rheumatoid arthritis. J Immunol. 2006;177:6471–6479. doi: 10.4049/jimmunol.177.9.6471. PubMed DOI

Zhu Y, Han S, Zhao H, Liang J, Zhai J, Wu Z, Qiu G. Comparative analysis of serum proteomes of degenerative scoliosis. J Orthop Res. 2011;29:1896–1903. doi: 10.1002/jor.21466. PubMed DOI

Scian R, Barrionuevo P, Rodriguez AM, Arriola BPC, García SC, Fossati CA, Giambartolomei GH, Delpino MV. Brucella abortus invasion of synoviocytes inhibits apoptosis and induces bone resorption through RANKL expression. Infect Immun. 2013;81:1940–1951. doi: 10.1128/IAI.01366-12. PubMed DOI PMC

Høgåsen K, Mollnes TE, Harboe M, Götze O, Hammer HB, Oppermann M. Terminal complement pathway activation and low lysis inhibitors in rheumatoid arthritis synovial fluid. J Rheumatol. 1995;22:24–28. PubMed

Cuida M, Legler DW, Eidsheim M, Jonsson R. Complement regulatory proteins in the salivary glands and saliva of Sjögren’s syndrome patients and healthy subjects. Clin Exp Rheumatol. 1997;15:615–623. PubMed

Falgarone G, Chiocchia G. Chapter 8: Clusterin: A multifacet protein at the crossroad of inflammation and autoimmunity. Adv Cancer Res. 2009;104:139–170. doi: 10.1016/S0065-230X(09)04008-1. PubMed DOI

Klokov D, Leskov K, Araki S, Zou Y, Goetz EM, Luo X, Willson D, Boothman DA. Low dose IR-induced IGF-1-sCLU expression: a p53-repressed expression cascade that interferes with TGFβ1 signaling to confer a pro-survival bystander effect. Oncogene. 2013;32:479–490. doi: 10.1038/onc.2012.64. PubMed DOI PMC

Aigelsreiter A, Pichler M, Pixner T, Janig E, Schuller M, Lackner C, Scheipl S, Beham A, Regauer S. Clusterin expression in elastofibroma dorsi. Histol Histopathol. 2013;28:597–603. PubMed

Falgarone G, Essabbani A, Dumont F, Cagnard N, Mistou S, Chiocchia G. Implication of clusterin in TNF-alpha response of rheumatoid synovitis: lesson from in vitro knock-down of clusterin in human synovial fibroblast cells. Physiol Genomics. 2012;44:229–235. doi: 10.1152/physiolgenomics.00095.2010. PubMed DOI

Talmon G, Wake L, Muirhead D. Podoplanin and clusterin are reliable markers of nonneoplastic synovium at various sites. Int J Surg Pathol. 2013;21:587–590. doi: 10.1177/1066896913492195. PubMed DOI

Kwon MJ, Ju TJ, Heo JY, Kim YW, Kim JY, Won KC, Kim JR, Bae YK, Park IS, Min BH, Lee IK, Park SY. Deficiency of clusterin exacerbates high-fat diet-induced insulin resistance in male mice. Endocrinology. 2014;155:2089–2101. doi: 10.1210/en.2013-1870. PubMed DOI

Seo JA, Kang MC, Yang WM, Hwang WM, Kim SS, Hong SH, Heo JI, Vijyakumar A, Pereira DML, Uner A, Huang H, Lee SH, Lima IS, Park KS, Kim MS, Dagon Y, Willnow TE, Aroda V, Ciaraldi TP, Henry RR, Kim YB. Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity. Nat Commun. 2020;11:2024. doi: 10.1038/s41467-020-15963-w. PubMed DOI PMC

Kropáčková T, Vernerová L, Štorkánová H, Horváthová V, Vokurková M, Klein M, Oreská S, Špiritović M, Heřmánková B, Kubínová K, Cerezo LA, Kryštůfková O, Mann H, Ukropec J, Ukropcová B, Zámečník J, Tomčík M, Vencovský J, Šenolt L. Clusterin is upregulated in serum and muscle tissue in idiopathic inflammatory myopathies and associates with clinical disease activity and cytokine profile. Clin Exp Rheumatol. 2021;39:1021–1032. doi: 10.55563/clinexprheumatol/k3vtg5. PubMed DOI

Aruwajoye OO, Kim HKW, Aswath PB. Bone apatite composition of necrotic trabecular bone in the femoral head of immature piglets. Calcif Tissue Int. 2015;96:324–334. doi: 10.1007/s00223-015-9959-7. PubMed DOI

Hsiao YM, Hu CC, Chen MF, Chang CH, Chiu YT, Chang Y. Serum Insufficiency Induces RANKL-Independent Osteoclast Formation during Developing Ischemic ONFH. Biomedicines. 2021;9:1–14. doi: 10.3390/biomedicines9060685. PubMed DOI PMC

Yu B, Yang Y, Liu H, Gong M, Millard RW, Wang YG, Ashraf M, Xu M. Clusterin/Akt Up-Regulation Is Critical for GATA-4 Mediated Cytoprotection of Mesenchymal Stem Cells against Ischemia Injury. PloS One. 2016;11:e0151542. doi: 10.1371/journal.pone.0151542. PubMed DOI PMC

Abdallah BM, Alzahrani AM, Kassem M. Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway. Bone. 2018;110:221–229. doi: 10.1016/j.bone.2018.02.018. PubMed DOI

Choi B, Kang SS, Kang SW, Min BH, Lee EJ, Song DH, Kim SM, Song Y, Yoon SY, Chang EJ. Secretory clusterin inhibits osteoclastogenesis by attenuating M-CSF-dependent osteoclast precursor cell proliferation. Biochem Biophys Res Commun. 2014;450:105–109. doi: 10.1016/j.bbrc.2014.05.074. PubMed DOI

Tarquini C, Pucci S, Scioli MG, Doldo E, Agostinelli S, D’Amico F, Bielli A, Ferlosio A, Caredda E, Tarantino U, Orlandi A. Clusterin exerts a cytoprotective and antioxidant effect in human osteoarthritic cartilage. Aging (Albany NY) 2020;12:10129–10146. doi: 10.18632/aging.103310. PubMed DOI PMC

Kumar S, Connor JR, Dodds RA, Halsey W, Van HM, Mao J, Sathe G, Mui P, Agarwal P, Badger AM, Lee JC, Gowen M, Lark MW. Identification and initial characterization of 5000 expressed sequenced tags (ESTs) each from adult human normal and osteoarthritic cartilage cDNA libraries. Osteoarthritis Cartilage. 2001;9:641–653. doi: 10.1053/joca.2001.0421. PubMed DOI

Bianchi VJ, Weber JF, Waldman SD, Backstein D, Kandel RA. Formation of hyaline cartilage tissue by passaged human osteoarthritic chondrocytes. Tissue Eng Part A. 2017;23:156–165. doi: 10.1089/ten.tea.2016.0262. PubMed DOI

McCarthy HS, Malda J, Richardson JB, Roberts S. Increased production of Clusterin in biopsies of repair tissue following autologous chondrocyte implantation. Cartilage. 2013;4:227–238. doi: 10.1177/1947603513477652. PubMed DOI PMC

Matta C, Fellows CR, Quasnichka H, Williams A, Jeremiasse B, Allaway D, Mobasheri A. Clusterin secretion is attenuated by the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α in models of cartilage degradation. J Orthop Res. 2021;39:1017–1029. doi: 10.1002/jor.24814. PubMed DOI

Ungsudechachai T, Honsawek S, Jittikoon J, Udomsinprasert W. Clusterin exacerbates interleukin-1beta-induced inflammation via suppressing PI3K/Akt pathway in human fibroblast-like synoviocytes of knee osteoarthritis. Sci Rep. 2022;12:9963. doi: 10.1038/s41598-022-14295-7. PubMed DOI PMC

Fukuda I, Ishihara T, Ohmachi S, Sakikawa I, Morita A, Ikeda M, Yamane S, Toyosaki-Maeda T, Takinami Y, Okamoto H, Numata Y, Fukui N. Potential plasma biomarkers for progression of knee osteoarthritis using glycoproteomic analysis coupled with a 2D-LC-MALDI system. Proteome Sci. 2012;10:36. doi: 10.1186/1477-5956-10-36. PubMed DOI PMC

Ungsudechachai T, Honsawek S, Jittikoon J, Udomsinprasert W. Clusterin is associated with systemic and synovial inflammation in knee osteoarthritis. Cartilage. 2020 doi: 10.1177/1947603520958149. 1947603520958149. PubMed DOI PMC

Ritter SY, Collins J, Krastins B, Sarracino D, Lopez M, Losina E, Aliprantis AO. Mass spectrometry assays of plasma biomarkers to predict radiographic progression of knee osteoarthritis. Arthritis Res Ther. 2014;16:456. doi: 10.1186/s13075-014-0456-6. PubMed DOI PMC

Barreto G, Soliymani R, Baumann M, Waris E, Eklund KK, Zenobi-Wong M, Lalowski M. Functional analysis of synovial fluid from osteoarthritic knee and carpometacarpal joints unravels different molecular profiles. Rheumatology (Oxford) 2019;58:897–907. doi: 10.1093/rheumatology/key232. PubMed DOI

Kalvaityte U, Matta C, Bernotiene E, Pushparaj PN, Kiapour AM, Mobasheri A. Exploring the translational potential of clusterin as a biomarker of early osteoarthritis. J Orthop Translat. 2022;32:77–84. doi: 10.1016/j.jot.2021.10.001. PubMed DOI PMC

Martin-Vaquero P, da Costa RC, Allen MJ, Moore SA, Keirsey JK, Green KB. Proteomic analysis of cerebrospinal fluid in canine cervical spondylomyelopathy. Spine. 2015;40:601–612. doi: 10.1097/BRS.0000000000000831. PubMed DOI PMC

Anjum A, Yazid MD, Fauzi DM, Idris J, Ng AMH, Selvi NA, Ismail OHR, Athi KRK, Lokanathan Y. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020;21:7533. doi: 10.3390/ijms21207533. PubMed DOI PMC

Anderson AJ, Najbauer J, Wencheng H, Wise Y, Stephanie R. Upregulation of complement inhibitors in association with vulnerable cells following contusion-induced spinal cord injury. J Neurotrauma. 2005;22:382–397. doi: 10.1089/neu.2005.22.382. PubMed DOI

Purmessur D, Schek RM, Abbott RD, Ballif BA, Godburn KE, Iatridis JC. Notochordal conditioned media from tissue increases proteoglycan accumulation and promotes a healthy nucleus pulposus phenotype in human mesenchymal stem cells. Arthritis Res Ther. 2011;13:R81. doi: 10.1186/ar3344. PubMed DOI PMC

Rao UN, Hood BL, Jones-Laughner JM, Sun M, Conrads TP. Distinct profiles of oxidative stress-related and matrix proteins in adult bone and soft tissue osteosarcoma and desmoid tumors: a proteomics study. Hum Pathol. 2013;44:725–733. doi: 10.1016/j.humpath.2012.06.023. PubMed DOI

Ma J, Gao W, Gao J. sCLU as prognostic biomarker and therapeutic target in osteosarcoma. Bioengineered. 2019;10:229–239. doi: 10.1080/21655979.2019.1621136. PubMed DOI PMC

Trougakos IP, So A, Jansen B, Gleave ME, Gonos ES. Silencing Expression of the Clusterin/Apolipoprotein J Gene in Human Cancer Cells Using Small Interfering RNA Induces Spontaneous Apoptosis, Reduced Growth Ability, and Cell Sensitization to Genotoxic and Oxidative Stress. Cancer Res. 2004;64:1834–1842. doi: 10.1158/0008-5472.CAN-03-2664. PubMed DOI

Lamoureux F, Baud’huin M, Ory B, Guiho R, Zoubeidi A, Gleave M, Heymann D, Rédini F. Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma. Oncotarget. 2014;5:7805–7819. doi: 10.18632/oncotarget.2308. PubMed DOI PMC

Liu K, He Q, Liao G, Han J. Identification of critical genes and gene interaction networks that mediate osteosarcoma metastasis to the lungs. Exp Ther Med. 2015;10:1796–1806. doi: 10.3892/etm.2015.2767. PubMed DOI PMC

Trougakos IP, Lourda M, Agiostratidou G, Kletsas D, Gonos ES. Differential effects of clusterin/apolipoprotein J on cellular growth and survival. Free Radic Biol Med. 2005;38:436–449. doi: 10.1016/j.freeradbiomed.2004.10.038. PubMed DOI

Yoshizawa Y, Nakao T, Tsuritani K, Yamada T, Watanabe N, Chiba A, Robinson WH, Miyake S. The importance of specific citrullinated clusterin and vimentin found in a multi-coloured bead-based citrulline-peptide array system in rheumatoid arthritis. Clin Exp Rheumatol. 2022;40:936–944. PubMed

Hughes-Austin JM, Gan RW, Deane KD, Weisman MH, Demoruelle MK, Sokolove J, Robinson WH, Holers VM, Norris JM, Ix JH. Association of antibodies to citrullinated protein antigens with blood pressure in first-degree relatives of rheumatoid arthritis patients: the studies of the etiology of rheumatoid arthritis. Am J Nephrol. 2017;46:481–487. doi: 10.1159/000485259. PubMed DOI PMC

Tedeschi SK, Cui J, Arkema EV, Robinson WH, Sokolove J, Lingampalli N, Sparks JA, Karlson EW, Costenbader KH. Elevated BMI and antibodies to citrullinated proteins interact to increase rheumatoid arthritis risk and shorten time to diagnosis: a nested case-control study of women in the nurses’ health studies. Semin Arthritis Rheum. 2017;46:692–698. doi: 10.1016/j.semarthrit.2016.09.001. PubMed DOI PMC

Qiao L, Deng C, Wang Q, Zhang W, Fei Y, Xu Y, Zhao Y, Li Y. Serum clusterin and complement factor H may be biomarkers differentiate primary sjogren’s syndrome with and without neuromyelitis optica spectrum disorder. Front Immunol. 2019;10:2527. doi: 10.3389/fimmu.2019.02527. PubMed DOI PMC

Polimeno L, Rossi R, Mastrodonato M, Montagnani M, Piscitelli D, Pesetti B, De BL, Girardi B, Resta L, Napoli A, Francavilla A. Augmenter of liver regeneration, a protective factor against ROS-induced oxidative damage in muscle tissue of mitochondrial myopathy affected patients. Int J Biochem Cell Biol. 2013;45:2410–2419. doi: 10.1016/j.biocel.2013.07.010. PubMed DOI

Pucci S, Greggi C, Polidoro C, Piro MC, Celi M, Feola M, Gasbarra E, Iundusi R, Mastrangeli F, Novelli G, Orlandi A, Tarantino U. Clusterin silencing restores myoblasts viability and down modulates the inflammatory process in osteoporotic disease. J Transl Med. 2019;17:118. doi: 10.1186/s12967-019-1868-5. PubMed DOI PMC

Connor JR, Kumar S, Sathe G, Mooney J, O’Brien SP, Mui P, Murdock PR, Gowen M, Lark MW. Clusterin expression in adult human normal and osteoarthritic articular cartilage. Osteoarthritis Cartilage. 2001;9:727–737. doi: 10.1053/joca.2001.0475. PubMed DOI

Khan IM, Salter DM, Bayliss MT, Thomson BM, Archer CW. Expression of clusterin in the superficial zone of bovine articular cartilage. Arthritis Rheum. 2001;44:1795–1799. doi: 10.1002/1529-0131(200108)44:8<1795::AID-ART316>3.0.CO;2-K. PubMed DOI