Skip to main content
SpringerLink
Log in

C-type lectin domain-containing protein CLEC3A regulates proliferation, regeneration and maintenance of nucleus pulposus cells

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

It is widely assumed that as connective tissue, the intervertebral disc (IVD) plays a crucial role in providing flexibility for the spinal column. The disc is comprised of three distinct tissues: the nucleus pulposus (NP), ligamentous annulus fibrous (AF) that surrounds the NP, and the hyaline cartilaginous endplates (CEP). Nucleus pulposus, composed of chondrocyte-like NP cells and its secreted gelatinous matrix, is critical for disc health and function. The NP matrix underwent dehydration accompanied by increasing fibrosis with age. The degeneration of matrix is almost impossible to repair, with the consequence of matrix stiffness and senescence of NP cells and intervertebral disc, suggesting the value of glycoproteins in extracellular matrix (ECM). Here, via database excavation and biological function screening, we investigated a C-type lectin protein, CLEC3A, which could support differentiation of chondrocytes as well as maintenance of NP cells and was essential to intervertebral disc homeostasis. Furthermore, mechanistic analysis revealed that CLEC3A could stimulate PI3K-AKT pathway to accelerate cell proliferation to further play part in NP cell regeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Huang YC, Urban JP, Luk KD (2014) Intervertebral disc regeneration: do nutrients lead the way? Nat Rev Rheumatol 10(9):561–566

    Article  Google Scholar 

  2. Rezwan K, Chen QZ, Blaker JJ et al (2006) Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials 27(18):3413–3431

    Article  CAS  Google Scholar 

  3. Urban JP, Roberts S (2003) Degeneration of the intervertebral disc. Arthritis Res Ther 5(3):120–130

    Article  Google Scholar 

  4. Priyadarshani P, Li Y, Yao L (2016) Advances in biological therapy for nucleus pulposus regeneration. Osteoarthr Cartil 24(2):206–212

    Article  CAS  Google Scholar 

  5. Vergroesen PP, Kingma I, Emanuel KS et al (2015) Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr Cartil 23(7):1057–1070

    Article  Google Scholar 

  6. Dowdell J, Erwin M, Choma T et al (2017) Intervertebral disk degeneration and repair. Neurosurgery 80(3S):S46–S54

    Article  Google Scholar 

  7. Song Y, Wang Y, Zhang Y et al (2017) Advanced glycation end products regulate anabolic and catabolic activities via NLRP3-inflammasome activation in human nucleus pulposus cells. J Cell Mol Med 21(7):1373–1387

    Article  CAS  Google Scholar 

  8. Drickamer K (1999) C-type lectin-like domains. Curr Opin Struct Biol 9(5):585–590

    Article  CAS  Google Scholar 

  9. Weis WI, Taylor ME, Drickamer K (1998) The C-type lectin superfamily in the immune system. Immunol Rev 163:19–34

    Article  CAS  Google Scholar 

  10. Wevers BA, Geijtenbeek TB, Gringhuis SI (2013) C-type lectin receptors orchestrate antifungal immunity. Future Microbiol 8(7):839–854

    Article  CAS  Google Scholar 

  11. Zelensky AN, Gready JE (2005) The C-type lectin-like domain superfamily. FEBS J 272(24):6179–6217

    Article  CAS  Google Scholar 

  12. Nasu J, Uto T, Fukaya T et al (2020) Pivotal role of the carbohydrate recognition domain in self-interaction of CLEC4A to elicit the ITIM-mediated inhibitory function in murine conventional dendritic cells in vitro. Int Immunol 32(10):673–682

    Article  CAS  Google Scholar 

  13. Weng TY, Li CJ, Li CY et al (2017) Skin delivery of Clec4a small hairpin rna elicited an effective antitumor response by enhancing CD8(+) immunity in vivo. Mol Therapy Nucl Acids 15(9):419–427

    Article  Google Scholar 

  14. Chen ST, Lin YL, Huang MT et al (2008) CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453(7195):672–676

    Article  CAS  Google Scholar 

  15. Yue R, Shen B, Morrison SJ (2016) Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton. Elife 5:e18782. https://doi.org/10.7554/eLife.18782

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wang M, Guo J, Zhang L et al (2020) Molecular structure, expression, and functional role of Clec11a in skeletal biology and cancers. J Cell Physiol 235(10):6357–6365

    Article  CAS  Google Scholar 

  17. Fukuhara H, Furukawa A, Maenaka K (2014) New binding face of C-type lectin-like domains. Structure 22(12):1694–1696

    Article  CAS  Google Scholar 

  18. Elezagic D, Morgelin M, Hermes G et al (2019) Antimicrobial peptides derived from the cartilage-specific C-type Lectin Domain Family 3 Member A (CLEC3A) potential in the prevention and treatment of septic arthritis. Osteoarthr Cartil 27(10):1564–1573

    Article  CAS  Google Scholar 

  19. Ren C, Pan R, Hou L et al (2020) Suppression of CLEC3A inhibits osteosarcoma cell proliferation and promotes their chemosensitivity through the AKT1/mTOR/HIF1alpha signaling pathway. Mol Med Rep 21(4):1739–1748

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang C, Smith MP, Zhou GK et al (2019) Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice. Cell Death Dis 10(10):754

    Article  CAS  Google Scholar 

  21. Kfoury Y, Scadden DT (2015) Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell 16(3):239–253

    Article  CAS  Google Scholar 

  22. Pinho S, Frenette PS (2019) Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol 20(5):303–320

    Article  CAS  Google Scholar 

  23. Miki M, Oono T, Fujimori N et al (2019) CLEC3A, MMP7, and LCN2 as novel markers for predicting recurrence in resected G1 and G2 pancreatic neuroendocrine tumors. Cancer Med 8(8):3748–3760

    Article  CAS  Google Scholar 

  24. Ruthard J, Hermes G, Hartmann U et al (2018) Identification of antibodies against extracellular matrix proteins in human osteoarthritis. Biochem Biophys Res Commun 503(3):1273–1277

    Article  CAS  Google Scholar 

  25. Lau D, Elezagic D, Hermes G et al (2018) The cartilage-specific lectin C-type lectin domain family 3 member A (CLEC3A) enhances tissue plasminogen activator-mediated plasminogen activation. J Biol Chem 293(1):203–214

    Article  CAS  Google Scholar 

  26. Hoxhaj G, Manning BD (2020) The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 20(2):74–88

    Article  CAS  Google Scholar 

  27. Peck SH, McKee KK, Tobias JW et al (2017) Whole transcriptome analysis of notochord-derived cells during embryonic formation of the nucleus pulposus. Sci Rep 7(1):10504

    Article  Google Scholar 

  28. Nerlich AG, Bachmeier BE, Boos N (2005) Expression of fibronectin and TGF-beta1 mRNA and protein suggest altered regulation of extracellular matrix in degenerated disc tissue. Eur Spine J 14(1):17–26

    Article  Google Scholar 

  29. Schroeder M, Viezens L, Schaefer C et al (2013) Chemokine profile of disc degeneration with acute or chronic pain. J Neurosurg Spine 18(5):496–503

    Article  Google Scholar 

  30. Abbott RD, Purmessur D, Monsey RD et al (2013) Degenerative grade affects the responses of human nucleus pulposus cells to link-N, CTGF, and TGFβ3. J Spinal Disord Tech 26(3):E86-94

    Article  Google Scholar 

  31. Huang F, Shi Q, Li Y et al (2018) HER2/EGFR-AKT signaling Switches TGFβ from inhibiting cell proliferation to promoting cell migration in breast cancer. Cancer Res 78(21):6073–6085

    Article  CAS  Google Scholar 

  32. Conery AR, Cao Y, Thompson EA et al (2004) Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 6(4):366–372

    Article  CAS  Google Scholar 

  33. Song K, Wang H, Krebs TL et al (2006) Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. Embo j 25(1):58–69

    Article  CAS  Google Scholar 

  34. Pfirrmann CW, Metzdorf A, Zanetti M et al (2001) Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976) 26(17):1873–1878

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the grants from National Natural Science Foundation (81972127, 81802216), Shanghai Science and Technology Fund (20DZ2201300), Incubating Program for Clinical Research and Innovation of Renji Hospital (PYZY16-010).

Author information

Author notes

  1. Xiuyuan Chen, Yucheng Ji and Fan Feng contributed equally to this work.

Authors and Affiliations

  1. Department of Spine Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Xiuyuan Chen, Yucheng Ji, Fan Feng, Zude Liu, Lie Qian, Hongxing Shen & Lifeng Lao

Authors
  1. Xiuyuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yucheng Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fan Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zude Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lie Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongxing Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lifeng Lao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LL designed experiments, YJ interpreted data; XC and FF performed most of the experiments; ZL assisted in some experiments; YJ provided the key materials; LQ was assisted in some discussion; XC and YJ wrote the manuscript; LL and Hongxing Shen provided the overall guidance.

Corresponding author

Correspondence to Lifeng Lao.

Ethics declarations

Conflict of interest

Xiuyuan Chen, Yucheng Ji, Fan Feng, Zude Liu, Lie Qian, Hongxing Shen and Lifeng Lao declare that they have no conflict of interest.

Ethical approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Ethics approval was obtained from the Institutional Review Board of Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19374 kb)

Supplementary file2 (XLSX 10 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Ji, Y., Feng, F. et al. C-type lectin domain-containing protein CLEC3A regulates proliferation, regeneration and maintenance of nucleus pulposus cells. Cell. Mol. Life Sci. 79, 435 (2022). https://doi.org/10.1007/s00018-022-04477-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04477-x

Keywords

Search

Navigation