Collagen: quantification, biomechanics and role of minor subtypes in cartilage

Abstract

Collagen is a ubiquitous biomaterial in vertebrate animals. Although each of its 28 subtypes contributes to the functions of many different tissues in the body, most studies on collagen or collagenous tissues have focused on only one or two subtypes. With recent developments in analytical chemistry, especially mass spectrometry, substantial advances have been made towards quantifying the different collagen subtypes in various tissues; however, high-throughput and low-cost methods for collagen-subtype quantification do not yet exist. In this Review, we introduce the roles of collagen subtypes and crosslinks and describe modern assays that enable a deep understanding of tissue physiology and disease states. Using cartilage as a model tissue, we describe the roles of major and minor collagen subtypes in detail, discuss known and unknown structure–function relationships and show how tissue engineers may harness the functional characteristics of collagen to engineer robust neotissues.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Collagen types of the human body.
Fig. 2: Lysyl oxidase pathway.
Fig. 3: Examples of quantitative assays for collagen and collagen crosslinks.
Fig. 4: Collagen structure and location in cartilage, and its role in cartilage development.
Fig. 5: Functional groups of collagen subtypes in cartilage.
Fig. 6: Broad applications for high-throughput, low-cost collagen quantification.

References

  1. 1.

    Whitslar, W. H. A study of the chemical composition of the dental pulp. Am. J. Dent. Sci. 23, 350–355 (1889).

    CAS  Google Scholar 

  2. 2.

    Lin, S. & Gu, L. Influence of crosslink density and stiffness on mechanical properties of type I collagen gel. Materials 8, 551–560 (2015).

    Google Scholar 

  3. 3.

    Eleswarapu, S. V., Responte, D. J. & Athanasiou, K. A. Tensile properties, collagen content, and crosslinks in connective tissues of the immature knee joint. PLoS ONE 6, e26178 (2011).

    CAS  Google Scholar 

  4. 4.

    Brüel, A., Ørtoft, G. & Oxlund, H. Inhibition of cross-links in collagen is associated with reduced stiffness of the aorta in young rats. Atherosclerosis 140, 135–145 (1998).

    Google Scholar 

  5. 5.

    Fang, M., Yuan, J., Peng, C. & Li, Y. Collagen as a double-edged sword in tumor progression. Tumour Biol. 35, 2871–2882 (2014).

    CAS  Google Scholar 

  6. 6.

    Xu, S. et al. The role of collagen in cancer: from bench to bedside. J. Transl. Med. 17, 309 (2019).

    Google Scholar 

  7. 7.

    Poole, A. R. et al. Type II collagen degradation and its regulation in articular cartilage in osteoarthritis. Ann. Rheum. Dis. 61, ii78–ii81 (2002).

    CAS  Google Scholar 

  8. 8.

    Landewé, R. B. M. et al. Arthritis instantaneously causes collagen type I and type II degradation in patients with early rheumatoid arthritis: a longitudinal analysis. Ann. Rheum. Dis. 65, 40–44 (2006).

    Google Scholar 

  9. 9.

    Kuivaniemi, H., Tromp, G. & Prockop, D. J. Mutations in collagen genes: causes of rare and some common diseases in humans. FASEB J. 5, 2052–2060 (1991).

    CAS  Google Scholar 

  10. 10.

    Arseni, L., Lombardi, A. & Orioli, D. From structure to phenotype: impact of collagen alterations on human health. Int. J. Mol. Sci. 19, 1407 (2018).

    Google Scholar 

  11. 11.

    Sorushanova, A. et al. The collagen suprafamily: from biosynthesis to advanced biomaterial development. Adv. Mater. 31, e1801651 (2019).

    Google Scholar 

  12. 12.

    Kadler, K. E., Hill, A. & Canty-Laird, E. G. Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr. Opin. Cell Biol. 20, 495–501 (2008).

    CAS  Google Scholar 

  13. 13.

    Shoulders, M. D. & Raines, R. T. Collagen structure and stability. Annu. Rev. Biochem. 78, 929–958 (2009). This review paper describes the structure and characteristics of collagen triple helices.

    CAS  Google Scholar 

  14. 14.

    Responte, D. J., Natoli, R. M. & Athanasiou, K. A. Collagens of articular cartilage: structure, function, and importance in tissue engineering. Crit. Rev. Biomed. Eng. 35, 363–411 (2007).

    Google Scholar 

  15. 15.

    Lin, K. et al. Advanced collagen-based biomaterials for regenerative biomedicine. Adv. Funct. Mater. 29, 1804943 (2019).

    Google Scholar 

  16. 16.

    Chang, S.-W. & Buehler, M. J. Molecular biomechanics of collagen molecules. Mater. Today 17, 70–76 (2014).

    CAS  Google Scholar 

  17. 17.

    Ricard-Blum, S. The collagen family. Cold Spring Harb. Perspect. Biol. 3, a004978 (2011).

    Google Scholar 

  18. 18.

    Sharma, U. et al. Structural basis of homo- and heterotrimerization of collagen I. Nat. Commun. 8, 14671 (2017).

    Google Scholar 

  19. 19.

    An, B. et al. Definition of the native and denatured type II collagen binding site for fibronectin using a recombinant collagen system. J. Biol. Chem. 289, 4941–4951 (2014).

    CAS  Google Scholar 

  20. 20.

    Pihlajamaa, T. et al. Characterization of recombinant human type IX collagen. Association of alpha chains into homotrimeric and heterotrimeric molecules. J. Biol. Chem. 274, 22464–22468 (1999).

    CAS  Google Scholar 

  21. 21.

    Eyre, D. R., Weis, M. A. & Wu, J.-J. Advances in collagen cross-link analysis. Methods 45, 65–74 (2008). This paper highlights methods for analysing crosslinked collagen peptides with LC-MS/MS and shows intermolecular crosslinks between collagen types IX and II.

    CAS  Google Scholar 

  22. 22.

    Siegel, R. C. Biosynthesis of collagen crosslinks: increased activity of purified lysyl oxidase with reconstituted collagen fibrils. Proc. Natl Acad. Sci. USA 71, 4826–4830 (1974).

    CAS  Google Scholar 

  23. 23.

    Barnard, K., Light, N. D., Sims, T. J. & Bailey, A. J. Chemistry of the collagen cross-links. Origin and partial characterization of a putative mature cross-link of collagen. Biochem. J. 244, 303–309 (1987).

    CAS  Google Scholar 

  24. 24.

    Robins, S. P. in Dynamics of Bone and Cartilage Metabolism (eds Seibel, M. J., Robins, S. P. & Bilezikian, J. P.) 41–53 (Elsevier, 2006).

  25. 25.

    Avery, N. C., Sims, T. J. & Bailey, A. J. Quantitative determination of collagen cross-links. Methods Mol. Biol. 522, 103–121 (2009).

    CAS  Google Scholar 

  26. 26.

    Saito, M. & Marumo, K. Effects of collagen crosslinking on bone material properties in health and disease. Calcif. Tissue Int. 97, 242–261 (2015).

    CAS  Google Scholar 

  27. 27.

    Eyre, D. R., Weis, M. A. & Wu, J.-J. Maturation of collagen ketoimine cross-links by an alternative mechanism to pyridinoline formation in cartilage. J. Biol. Chem. 285, 16675–16682 (2010).

    CAS  Google Scholar 

  28. 28.

    Willett, T. L., Kandel, R., De Croos, J. N. A., Avery, N. C. & Grynpas, M. D. Enhanced levels of non-enzymatic glycation and pentosidine crosslinking in spontaneous osteoarthritis progression. Osteoarthr. Cartil. 20, 736–744 (2012).

    CAS  Google Scholar 

  29. 29.

    Steinhart, H., Bosselmann, A. & Moeller, C. Determination of pyridinolines in bovine collagenous tissues. J. Agric. Food Chem. 42, 1943–1947 (1994).

    CAS  Google Scholar 

  30. 30.

    Tan, C. I., Kent, G. N., Randall, A. G., Edmondston, S. J. & Singer, K. P. Age-related changes in collagen, pyridinoline, and deoxypyridinoline in normal human thoracic intervertebral discs. J. Gerontol. A. Biol. Sci. Med. Sci. 58, B387–B393 (2003).

    Google Scholar 

  31. 31.

    Delmas, P. D., Schlemmer, A., Gineyts, E., Riis, B. & Christiansen, C. Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis. J. Bone Miner. Res. 6, 639–644 (1991).

    CAS  Google Scholar 

  32. 32.

    Lindert, U. et al. Urinary pyridinoline cross-links as biomarkers of osteogenesis imperfecta. Orphanet J. Rare Dis. 10, 104 (2015).

    Google Scholar 

  33. 33.

    Takeuchi, S., Arai, K., Saitoh, H., Yoshida, K. & Miura, M. Urinary pyridinoline and deoxypyridinoline as potential markers of bone metastasis in patients with prostate cancer. J. Urol. 156, 1691–1695 (1996).

    CAS  Google Scholar 

  34. 34.

    Siegfried, M. Reticulin and collagen. J. Physiol. 28, 319–324 (1902).

    CAS  Google Scholar 

  35. 35.

    Tebb, M. C. Reticulin and collagen. J. Physiol. 27, 463–472 (1902).

    CAS  Google Scholar 

  36. 36.

    Neuman, R. E. & Logan, M. A. The determination of hydroxyproline. J. Biol. Chem. 184, 299–306 (1950).

    CAS  Google Scholar 

  37. 37.

    Reddy, G. K. & Enwemeka, C. S. A simplified method for the analysis of hydroxyproline in biological tissues. Clin. Biochem. 29, 225–229 (1996).

    CAS  Google Scholar 

  38. 38.

    Cissell, D. D., Link, J. M., Hu, J. C. & Athanasiou, K. A. A modified hydroxyproline assay based on hydrochloric acid in Ehrlich’s solution accurately measures tissue collagen content. Tissue Eng. Part C Methods 23, 243–250 (2017). This paper describes the most recent edition of the photometric hydroxyproline assay, which uses safer and less expensive materials, without sacrificing assay sensitivity.

    CAS  Google Scholar 

  39. 39.

    Caetano, G. F., Fronza, M., Leite, M. N., Gomes, A. & Frade, M. A. C. Comparison of collagen content in skin wounds evaluated by biochemical assay and by computer-aided histomorphometric analysis. Pharm. Biol. 54, 2555–2559 (2016).

    CAS  Google Scholar 

  40. 40.

    Kliment, C. R., Englert, J. M., Crum, L. P. & Oury, T. D. A novel method for accurate collagen and biochemical assessment of pulmonary tissue utilizing one animal. Int. J. Clin. Exp. Pathol. 4, 349–355 (2011).

    Google Scholar 

  41. 41.

    Stoilov, I., Starcher, B. C., Mecham, R. P. & Broekelmann, T. J. Measurement of elastin, collagen, and total protein levels in tissues. Methods Cell Biol. 143, 133–146 (2018).

    Google Scholar 

  42. 42.

    Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).

    CAS  Google Scholar 

  43. 43.

    Wu, J. et al. Extraction and isolation of type I, III and V collagens and their SDS-PAGE analyses. Trans. Tianjin Univ. 17, 111–117 (2011).

    CAS  Google Scholar 

  44. 44.

    Hayashi, T. & Nagai, Y. Separation of the α chains of type I and III collagens by SDS-polyacrylamide gel electrophoresis. J. Biochem. 86, 453–459 (1979).

    CAS  Google Scholar 

  45. 45.

    Vincent, S. G., Cunningham, P. R., Stephens, N. L., Halayko, A. J. & Fisher, J. T. Quantitative densitometry of proteins stained with coomassie blue using a Hewlett Packard scanjet scanner and Scanplot software. Electrophoresis 18, 67–71 (1997).

    CAS  Google Scholar 

  46. 46.

    Eyre, D. R., Koob, T. J. & Van Ness, K. P. Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal. Biochem. 137, 380–388 (1984).

    CAS  Google Scholar 

  47. 47.

    Saito, M., Marumo, K., Fujii, K. & Ishioka, N. Single-column high-performance liquid chromatographic-fluorescence detection of immature, mature, and senescent cross-links of collagen. Anal. Biochem. 253, 26–32 (1997).

    CAS  Google Scholar 

  48. 48.

    Robins, S. P., Stewart, P., Astbury, C. & Bird, H. A. Measurement of the cross linking compound, pyridinoline, in urine as an index of collagen degradation in joint disease. Ann. Rheum. Dis. 45, 969–973 (1986).

    CAS  Google Scholar 

  49. 49.

    Robins, S. P. et al. Direct, enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption. J. Bone Miner. Res. 9, 1643–1649 (1994).

    CAS  Google Scholar 

  50. 50.

    Taneda, S. & Monnier, V. M. ELISA of pentosidine, an advanced glycation end product, in biological specimens. Clin. Chem. 40, 1766–1773 (1994).

    CAS  Google Scholar 

  51. 51.

    Sutandy, F. X. R., Qian, J., Chen, C.-S. & Zhu, H. Overview of protein microarrays. Curr. Protoc. Protein Sci. 72, 27.1.1–27.1.16 (2013).

    Google Scholar 

  52. 52.

    Kuschel, C. et al. Cell adhesion profiling using extracellular matrix protein microarrays. Biotechniques 40, 523–531 (2006).

    CAS  Google Scholar 

  53. 53.

    Baker, H. N., Murphy, R., Lopez, E. & Garcia, C. Conversion of a capture ELISA to a Luminex xMAP assay using a multiplex antibody screening method. J. Vis. Exp. 65, e4084 (2012).

    Google Scholar 

  54. 54.

    Elshal, M. F. & McCoy, J. P. Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods 38, 317–323 (2006).

    CAS  Google Scholar 

  55. 55.

    Kim, C. H. et al. Stability and reproducibility of proteomic profiles measured with an aptamer-based platform. Sci. Rep. 8, 8382 (2018).

    Google Scholar 

  56. 56.

    Coghlan, R. F. et al. A degradation fragment of type X collagen is a real-time marker for bone growth velocity. Sci. Transl. Med. 9, eaan4669 (2017).

    Google Scholar 

  57. 57.

    Koolmees, P. A. & Bijker, P. G. Histometric and chemical methods for determining collagen in meats. Vet. Q. 7, 84–90 (1985).

    CAS  Google Scholar 

  58. 58.

    Grimm, P. C. et al. Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function. J. Am. Soc. Nephrol. 14, 1662–1668 (2003).

    Google Scholar 

  59. 59.

    Brigger, D. & Muckle, R. J. Comparison of Sirius red and Congo red as stains for amyloid in animal tissues. J. Histochem. Cytochem. 23, 84–88 (1975).

    CAS  Google Scholar 

  60. 60.

    Coelho, P. G. B., de Souza, M. V., Conceição, L. G., Viloria, M. I. V. & Bedoya, S. A. O. Evaluation of dermal collagen stained with picrosirius red and examined under polarized light microscopy. An. Bras. Dermatol. 93, 415–418 (2018).

    Google Scholar 

  61. 61.

    Nagai, M. et al. Alteration of cartilage surface collagen fibers differs locally after immobilization of knee joints in rats. J. Anat. 226, 447–457 (2015).

    CAS  Google Scholar 

  62. 62.

    Schmid, T. M. & Linsenmayer, T. F. Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. J. Cell Biol. 100, 598–605 (1985).

    CAS  Google Scholar 

  63. 63.

    Agarwal, P. et al. Collagen XII and XIV, new partners of cartilage oligomeric matrix protein in the skin extracellular matrix suprastructure. J. Biol. Chem. 287, 22549–22559 (2012).

    CAS  Google Scholar 

  64. 64.

    Yakovlev, D. D. et al. Quantitative mapping of collagen fiber alignment in thick tissue samples using transmission polarized-light microscopy. J. Biomed. Opt. 21, 071111 (2016).

    Google Scholar 

  65. 65.

    Chen, X., Nadiarynkh, O., Plotnikov, S. & Campagnola, P. J. Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure. Nat. Protoc. 7, 654–669 (2012).

    CAS  Google Scholar 

  66. 66.

    Keikhosravi, A. et al. Quantification of collagen organization in histopathology samples using liquid crystal based polarization microscopy. Biomed. Opt. Express 8, 4243–4256 (2017).

    CAS  Google Scholar 

  67. 67.

    Ghazanfari, S., Driessen-Mol, A., Strijkers, G. J., Baaijens, F. P. T. & Bouten, C. V. C. The evolution of collagen fiber orientation in engineered cardiovascular tissues visualized by diffusion tensor imaging. PLoS ONE 10, e0127847 (2015).

    Google Scholar 

  68. 68.

    Starborg, T., Lu, Y., Kadler, K. E. & Holmes, D. F. Electron microscopy of collagen fibril structure in vitro and in vivo including three-dimensional reconstruction. Methods Cell Biol. 88, 319–345 (2008).

    CAS  Google Scholar 

  69. 69.

    Starborg, T. et al. Using transmission electron microscopy and 3View to determine collagen fibril size and three-dimensional organization. Nat. Protoc. 8, 1433–1448 (2013).

    Google Scholar 

  70. 70.

    Changoor, A. et al. Structural characteristics of the collagen network in human normal, degraded and repair articular cartilages observed in polarized light and scanning electron microscopies. Osteoarthr. Cartil. 19, 1458–1468 (2011).

    CAS  Google Scholar 

  71. 71.

    Ruozi, B. et al. Intact collagen and atelocollagen sponges: characterization and ESEM observation. Mater. Sci. Eng. C 27, 802–810 (2007).

    CAS  Google Scholar 

  72. 72.

    Snellman, A. et al. A short sequence in the N-terminal region is required for the trimerization of type XIII collagen and is conserved in other collagenous transmembrane proteins. EMBO J. 19, 5051–5059 (2000).

    CAS  Google Scholar 

  73. 73.

    Manferdini, C. et al. Immunoelectron microscopic localization of collagen type XV during human mesenchymal stem cells mineralization. Connect. Tissue Res. 59, 42–45 (2018).

    CAS  Google Scholar 

  74. 74.

    Plumb, D. A. et al. Collagen XXVII is developmentally regulated and forms thin fibrillar structures distinct from those of classical vertebrate fibrillar collagens. J. Biol. Chem. 282, 12791–12795 (2007).

    CAS  Google Scholar 

  75. 75.

    Ranjit, S. et al. Imaging fibrosis and separating collagens using second harmonic generation and phasor approach to fluorescence lifetime imaging. Sci. Rep. 5, 13378 (2015).

    CAS  Google Scholar 

  76. 76.

    Haudenschild, A. K. et al. Nondestructive fluorescence lifetime imaging and time-resolved fluorescence spectroscopy detect cartilage matrix depletion and correlate with mechanical properties. Eur. Cell. Mater. 36, 30–43 (2018).

    CAS  Google Scholar 

  77. 77.

    Haudenschild, A. K. et al. Non-destructive detection of matrix stabilization correlates with enhanced mechanical properties of self-assembled articular cartilage. J. Tissue Eng. Regen. Med. 13, 637–648 (2019).

    CAS  Google Scholar 

  78. 78.

    Sherlock, B. E. et al. Nondestructive assessment of collagen hydrogel cross-linking using time-resolved autofluorescence imaging. J. Biomed. Opt. 23, 1 (2018).

    Google Scholar 

  79. 79.

    de Campos Vidal, B. & Mello, M. L. S. Collagen type I amide I band infrared spectroscopy. Micron 42, 283–289 (2011).

    Google Scholar 

  80. 80.

    Belbachir, K., Noreen, R., Gouspillou, G. & Petibois, C. Collagen types analysis and differentiation by FTIR spectroscopy. Anal. Bioanal. Chem. 395, 829–837 (2009).

    CAS  Google Scholar 

  81. 81.

    Bergholt, M. S., Serio, A. & Albro, M. B. Raman spectroscopy: guiding light for the extracellular matrix. Front. Bioeng. Biotechnol. 7, 303 (2019).

    Google Scholar 

  82. 82.

    Albro, M. B. et al. Raman spectroscopic imaging for quantification of depth-dependent and local heterogeneities in native and engineered cartilage. NPJ Regen. Med. 3, 3 (2018).

    CAS  Google Scholar 

  83. 83.

    Ye, H. et al. Burn-related collagen conformational changes in ex vivo porcine skin using Raman spectroscopy. Sci. Rep. 9, 19138 (2019).

    CAS  Google Scholar 

  84. 84.

    Nguyen, T. T. et al. Characterization of type I and IV collagens by Raman microspectroscopy: identification of spectral markers of the dermo-epidermal junction. J. Spectrosc. 27, 421–427 (2012).

    CAS  Google Scholar 

  85. 85.

    Marcu, L., Cohen, D., Maarek, J.-M. I. & Grundfest, W. S. Characterization of type I, II, III, IV, and V collagens by time-resolved laser-induced fluorescence spectroscopy. Optical Biopsy III 3917, 93–101 (2000).

    CAS  Google Scholar 

  86. 86.

    Sun, Y. et al. Development of a dual-modal tissue diagnostic system combining time-resolved fluorescence spectroscopy and ultrasonic backscatter microscopy. Rev. Sci. Instrum. 80, 065104 (2009).

    Google Scholar 

  87. 87.

    Colgrave, M. L., Allingham, P. G., Tyrrell, K. & Jones, A. Multiple reaction monitoring for the accurate quantification of amino acids: using hydroxyproline to estimate collagen content. Methods Mol. Biol. 2030, 33–45 (2019).

    CAS  Google Scholar 

  88. 88.

    Nimptsch, A. et al. Quantitative analysis of denatured collagen by collagenase digestion and subsequent MALDI-TOF mass spectrometry. Cell Tissue Res. 343, 605–617 (2011). This paper uses MALDI-TOF mass spectrometry to quantify glycine–proline–hydroxyproline tripeptides as a more sensitive method than the hydroxyproline assay.

    CAS  Google Scholar 

  89. 89.

    Yoshida, K. et al. Quantitative evaluation of collagen crosslinks and corresponding tensile mechanical properties in mouse cervical tissue during normal pregnancy. PLoS ONE 9, e112391 (2014).

    Google Scholar 

  90. 90.

    Naffa, R. et al. Rapid analysis of pyridinoline and deoxypyridinoline in biological samples by liquid chromatography with mass spectrometry and a silica hydride column. J. Sep. Sci. 42, 1482–1488 (2019).

    CAS  Google Scholar 

  91. 91.

    Kovacevic, I., Pokrajac, M., Miljkovic, B., Jovanovic, D. & Prostran, M. Comparison of liquid chromatography with fluorescence detection to liquid chromatography–mass spectrometry for the determination of fluoxetine and norfluoxetine in human plasma. J. Chromatogr. B 830, 372–376 (2006).

    CAS  Google Scholar 

  92. 92.

    Lin, H., Goodin, S., Strair, R. K., DiPaola, R. S. & Gounder, M. K. Comparison of LC-MS assay and HPLC assay of busulfan in clinical pharmacokinetics studies. ISRN Anal. Chem. 2012, 198683 (2012).

    Google Scholar 

  93. 93.

    Santa, T. Recent advances in analysis of glutathione in biological samples by high-performance liquid chromatography: a brief overview. Drug Discov. Ther. 7, 172–177 (2013).

    CAS  Google Scholar 

  94. 94.

    Dreisewerd, K., Rohlfing, A., Spottke, B., Urbanke, C. & Henkel, W. Characterization of whole fibril-forming collagen proteins of types I, III, and V from fetal calf skin by infrared matrix-assisted laser desorption ionization mass spectrometry. Anal. Chem. 76, 3482–3491 (2004).

    CAS  Google Scholar 

  95. 95.

    Pataridis, S., Eckhardt, A., Mikulikova, K., Sedlakova, P. & Miksik, I. Determination and quantification of collagen types in tissues using HPLC-MS/MS. Curr. Anal. Chem. 5, 316–323 (2009).

    CAS  Google Scholar 

  96. 96.

    Wang, Y. et al. Quantitative proteomics analysis of cartilage response to mechanical injury and cytokine treatment. Matrix Biol. 63, 11–22 (2017).

    CAS  Google Scholar 

  97. 97.

    Kumazawa, Y., Taga, Y., Iwai, K. & Koyama, Y.-I. A rapid and simple LC-MS method using collagen marker peptides for identification of the animal source of leather. J. Agric. Food Chem. 64, 6051–6057 (2016).

    CAS  Google Scholar 

  98. 98.

    Wiese, S., Reidegeld, K. A., Meyer, H. E. & Warscheid, B. Protein labeling by iTRAQ: a new tool for quantitative mass spectrometry in proteome research. Proteomics 7, 1004–1004 (2007).

    CAS  Google Scholar 

  99. 99.

    Lanucara, F. & Eyers, C. E. Mass spectrometric-based quantitative proteomics using SILAC. Methods Enzymol. 500, 133–150 (2011).

    CAS  Google Scholar 

  100. 100.

    Zhang, L. & Elias, J. E. Relative protein quantification using tandem mass tag mass spectrometry. Methods Mol. Biol. 1550, 185–198 (2017).

    CAS  Google Scholar 

  101. 101.

    Ye, X., Luke, B., Andresson, T. & Blonder, J. 18O stable isotope labeling in MS-based proteomics. Brief. Funct. Genomic. Proteomic. 8, 136–144 (2009).

    CAS  Google Scholar 

  102. 102.

    Zhu, W., Smith, J. W. & Huang, C.-M. Mass spectrometry-based label-free quantitative proteomics. J. Biomed. Biotechnol. 2010, 840518 (2010).

    Google Scholar 

  103. 103.

    Dresner, E. & Schubert, M. The comparative susceptibility to collagenase and trypsin of collagen, soluble collagens and renal basement membrane. J. Histochem. Cytochem. 3, 360–368 (1955).

    CAS  Google Scholar 

  104. 104.

    Krey, J. F. et al. Accurate label-free protein quantitation with high- and low-resolution mass spectrometers. J. Proteome Res. 13, 1034–1044 (2014).

    CAS  Google Scholar 

  105. 105.

    Cox, J. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell. Proteom. 13, 2513–2526 (2014).

    CAS  Google Scholar 

  106. 106.

    Önnerfjord, P., Khabut, A., Reinholt, F. P., Svensson, O. & Heinegård, D. Quantitative proteomic analysis of eight cartilaginous tissues reveals characteristic differences as well as similarities between subgroups. J. Biol. Chem. 287, 18913–18924 (2012). This paper shows a wide proteomics analysis on several types of cartilage. iTRAQ and LC-MS/MS technologies were used for relative quantification of many ECM molecules.

    Google Scholar 

  107. 107.

    Lourido, L. et al. Quantitative proteomic profiling of human articular cartilage degradation in osteoarthritis. J. Proteome Res. 13, 6096–6106 (2014).

    CAS  Google Scholar 

  108. 108.

    Frantzi, M. et al. Discovery and validation of urinary biomarkers for detection of renal cell carcinoma. J. Proteomics 98, 44–58 (2014).

    CAS  Google Scholar 

  109. 109.

    van Huizen, N. A. et al. Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue. J. Biol. Chem. 294, 281–289 (2019).

    Google Scholar 

  110. 110.

    Huey, D. J., Hu, J. C. & Athanasiou, K. A. Unlike bone, cartilage regeneration remains elusive. Science 338, 917–921 (2012).

    CAS  Google Scholar 

  111. 111.

    Athanasiou, K. A., Darling, E. M., Hu, J. C., DuRaine, G. D. & Hari Reddi, A. Articular Cartilage (CRC Press, 2017).

  112. 112.

    Sophia Fox, A. J., Bedi, A. & Rodeo, S. A. The basic science of articular cartilage: structure, composition, and function. Sports Health 1, 461–468 (2009). This review paper provides a thorough overview of articular cartilage, its zonal variations and its biomechanical functions.

    Google Scholar 

  113. 113.

    Almarza, A. J. & Athanasiou, K. A. Design characteristics for the tissue engineering of cartilaginous tissues. Ann. Biomed. Eng. 32, 2–17 (2004).

    Google Scholar 

  114. 114.

    Makris, E. A., Hadidi, P. & Athanasiou, K. A. The knee meniscus: structure–function, pathophysiology, current repair techniques, and prospects for regeneration. Biomaterials 32, 7411–7431 (2011).

    CAS  Google Scholar 

  115. 115.

    Kuroda, S. et al. Biomechanical and biochemical characteristics of the mandibular condylar cartilage. Osteoarthr. Cartil. 17, 1408–1415 (2009).

    CAS  Google Scholar 

  116. 116.

    Singh, M. & Detamore, M. S. Biomechanical properties of the mandibular condylar cartilage and their relevance to the TMJ disc. J. Biomech. 42, 405–417 (2009).

    CAS  Google Scholar 

  117. 117.

    Mithoefer, K., McAdams, T., Williams, R. J., Kreuz, P. C. & Mandelbaum, B. R. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am. J. Sports Med. 37, 2053–2063 (2009).

    Google Scholar 

  118. 118.

    Bos, E. J. et al. Structural and mechanical comparison of human ear, alar, and septal cartilage. Plast. Reconstr. Surg. Glob. Open. 6, e1610 (2018).

    Google Scholar 

  119. 119.

    Griffin, M. F., Premakumar, Y., Seifalian, A. M., Szarko, M. & Butler, P. E. M. Biomechanical characterisation of the human auricular cartilages; implications for tissue engineering. Ann. Biomed. Eng. 44, 3460–3467 (2016).

    CAS  Google Scholar 

  120. 120.

    Naumann, A. et al. Immunochemical and mechanical characterization of cartilage subtypes in rabbit. J. Histochem. Cytochem. 50, 1049–1058 (2002).

    CAS  Google Scholar 

  121. 121.

    Madsen, K., von der Mark, K., van Menxel, M. & Friberg, U. Analysis of collagen types synthesized by rabbit ear cartilage chondrocytes in vivo and in vitro. Biochem. J. 221, 189–196 (1984).

    CAS  Google Scholar 

  122. 122.

    Setton, L. A., Elliott, D. M. & Mow, V. C. Altered mechanics of cartilage with osteoarthritis: human osteoarthritis and an experimental model of joint degeneration. Osteoarthr. Cartil. 7, 2–14 (1999).

    CAS  Google Scholar 

  123. 123.

    Miosge, N., Hartmann, M., Maelicke, C. & Herken, R. Expression of collagen type I and type II in consecutive stages of human osteoarthritis. Histochem. Cell Biol. 122, 229–236 (2004).

    CAS  Google Scholar 

  124. 124.

    Lahm, A. et al. Changes in content and synthesis of collagen types and proteoglycans in osteoarthritis of the knee joint and comparison of quantitative analysis with Photoshop-based image analysis. Arch. Orthop. Trauma Surg. 130, 557–564 (2010).

    Google Scholar 

  125. 125.

    Hosseininia, S. et al. Evidence for enhanced collagen type III deposition focally in the territorial matrix of osteoarthritic hip articular cartilage. Osteoarthr. Cartil. 24, 1029–1035 (2016).

    CAS  Google Scholar 

  126. 126.

    Heinemeier, K. M. Type II collagen; designed to last a lifetime? Osteoarthr. Cartil. 25, S5 (2017).

    Google Scholar 

  127. 127.

    Owings, M. F. & Kozak, L. J. Ambulatory and inpatient procedures in the United States, 1996. Vital Health Stat. 13, 1–119 (1998).

    Google Scholar 

  128. 128.

    Moseley, J. B. et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N. Engl. J. Med. 347, 81–88 (2002).

    Google Scholar 

  129. 129.

    Koh, J. L., Wirsing, K., Lautenschlager, E. & Zhang, L.-O. The effect of graft height mismatch on contact pressure following osteochondral grafting: a biomechanical study. Am. J. Sports Med. 32, 317–320 (2004).

    Google Scholar 

  130. 130.

    Khan, I. M., Gilbert, S. J., Singhrao, S. K., Duance, V. C. & Archer, C. W. Cartilage integration: evaluation of the reasons for failure of integration during cartilage repair. A review. Eur. Cell. Mater. 16, 26–39 (2008).

    CAS  Google Scholar 

  131. 131.

    Makris, E. A., Gomoll, A. H., Malizos, K. N., Hu, J. C. & Athanasiou, K. A. Repair and tissue engineering techniques for articular cartilage. Nat. Rev. Rheumatol. 11, 21–34 (2015).

    CAS  Google Scholar 

  132. 132.

    Zhang, Z. et al. Matrix-induced autologous chondrocyte implantation for the treatment of chondral defects of the knees in Chinese patients. Drug Des. Devel. Ther. 8, 2439–2448 (2014).

    Google Scholar 

  133. 133.

    Frisbie, D. D. et al. Early events in cartilage repair after subchondral bone microfracture. Clin. Orthop. Relat. Res. 407, 215–227 (2003).

    Google Scholar 

  134. 134.

    Barber, F. A. What is the terrible triad? Arthroscopy 8, 19–22 (1992).

    CAS  Google Scholar 

  135. 135.

    LeResche, L. Epidemiology of temporomandibular disorders: implications for the investigation of etiologic factors. Crit. Rev. Oral Biol. Med. 8, 291–305 (1997).

    CAS  Google Scholar 

  136. 136.

    Murphy, M. K., MacBarb, R. F., Wong, M. E. & Athanasiou, K. A. Temporomandibular joint disorders: a review of etiology, clinical management, and tissue engineering strategies. Int. J. Oral Maxillofac. Implants 28, e393–e414 (2013).

    Google Scholar 

  137. 137.

    Urban, J. P. G. & Roberts, S. Degeneration of the intervertebral disc. Arthritis Res. Ther. 5, 120 (2003).

    Google Scholar 

  138. 138.

    Luoma, K. et al. Low back pain in relation to lumbar disc degeneration. Spine 25, 487–492 (2000).

    CAS  Google Scholar 

  139. 139.

    Maniadakis, N. & Gray, A. The economic burden of back pain in the UK. Pain 84, 95–103 (2000).

    CAS  Google Scholar 

  140. 140.

    Ha, A. Y., Shalvoy, R. M., Voisinet, A., Racine, J. & Aaron, R. K. Controversial role of arthroscopic meniscectomy of the knee: a review. World J. Orthop. 7, 287–292 (2016).

    Google Scholar 

  141. 141.

    Miloro, M. & Henriksen, B. Discectomy as the primary surgical option for internal derangement of the temporomandibular joint. J. Oral Maxillofac. Surg. 68, 782–789 (2010).

    Google Scholar 

  142. 142.

    Thorlund, J. B. et al. Patient reported outcomes in patients undergoing arthroscopic partial meniscectomy for traumatic or degenerative meniscal tears: comparative prospective cohort study. BMJ 356, j356 (2017).

    Google Scholar 

  143. 143.

    Illien-Jünger, S. et al. Detrimental effects of discectomy on intervertebral disc biology can be decelerated by growth factor treatment during surgery: a large animal organ culture model. Spine J. 14, 2724–2732 (2014).

    Google Scholar 

  144. 144.

    Kwon, H. et al. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nat. Rev. Rheumatol. 15, 550–570 (2019).

    Google Scholar 

  145. 145.

    Higashioka, M. M., Chen, J. A., Hu, J. C. & Athanasiou, K. A. Building an anisotropic meniscus with zonal variations. Tissue Eng. Part A 20, 294–302 (2014).

    Google Scholar 

  146. 146.

    Cao, Y., Vacanti, J. P., Paige, K. T., Upton, J. & Vacanti, C. A. Transplantation of chondrocytes utilizing a polymer-cell construct to produce tissue-engineered cartilage in the shape of a human ear. Plast. Reconstr. Surg. 100, 297–302 (1997).

    CAS  Google Scholar 

  147. 147.

    Little, C. J., Bawolin, N. K. & Chen, X. Mechanical properties of natural cartilage and tissue-engineered constructs. Tissue Eng. Part B Rev. 17, 213–227 (2011).

    CAS  Google Scholar 

  148. 148.

    Salinas, E. Y., Hu, J. C. & Athanasiou, K. A guide for using mechanical stimulation to enhance tissue-engineered articular cartilage properties. Tissue Eng. Part B Rev. 24, 345–358 (2018).

    Google Scholar 

  149. 149.

    Pulkkinen, H. J. et al. Repair of osteochondral defects with recombinant human type II collagen gel and autologous chondrocytes in rabbit. Osteoarthr. Cartil. 21, 481–490 (2013).

    CAS  Google Scholar 

  150. 150.

    Matsiko, A., Levingstone, T. J., O’Brien, F. J. & Gleeson, J. P. Addition of hyaluronic acid improves cellular infiltration and promotes early-stage chondrogenesis in a collagen-based scaffold for cartilage tissue engineering. J. Mech. Behav. Biomed. Mater. 11, 41–52 (2012).

    CAS  Google Scholar 

  151. 151.

    Munir, N. & Callanan, A. Novel phase separated polycaprolactone/collagen scaffolds for cartilage tissue engineering. Biomed. Mater. 13, 051001 (2018).

    CAS  Google Scholar 

  152. 152.

    Corradetti, B. et al. Immune tuning scaffold for the local induction of a pro-regenerative environment. Sci. Rep. 7, 17030 (2017).

    Google Scholar 

  153. 153.

    Boehler, R. M., Graham, J. G. & Shea, L. D. Tissue engineering tools for modulation of the immune response. Biotechniques 51, 239–240 (2011).

    CAS  Google Scholar 

  154. 154.

    Irawan, V., Sung, T.-C., Higuchi, A. & Ikoma, T. Collagen scaffolds in cartilage tissue engineering and relevant approaches for future development. Tissue Eng. Regen. Med. 15, 673–697 (2018).

    CAS  Google Scholar 

  155. 155.

    Moutos, F. T. & Guilak, F. Composite scaffolds for cartilage tissue engineering. Biorheology 45, 501–512 (2008).

    Google Scholar 

  156. 156.

    Eyre, D. Collagen of articular cartilage. Arthritis Res. 4, 30–35 (2002).

    CAS  Google Scholar 

  157. 157.

    Eyre, D. R. & Wu, J. J. Collagen of fibrocartilage: a distinctive molecular phenotype in bovine meniscus. FEBS Lett. 158, 265–270 (1983).

    CAS  Google Scholar 

  158. 158.

    Luo, Y. et al. The minor collagens in articular cartilage. Protein Cell 8, 560–572 (2017). This review paper describes the minor collagens found in articular cartilage, including the molecules to which they bind, and which collagens may be used as biomarkers of joint diseases.

    CAS  Google Scholar 

  159. 159.

    Johns, D. E. & Athanasiou, K. A. Design characteristics for temporomandibular joint disc tissue engineering: learning from tendon and articular cartilage. Proc. Inst. Mech. Eng. H 221, 509–526 (2007).

    CAS  Google Scholar 

  160. 160.

    Eyre, D. R. & Muir, H. E. Types I and II collagens in intervertebral disc. Interchanging radial distributions in annulus fibrosus. Biochem. J. 157, 267–270 (1976).

    CAS  Google Scholar 

  161. 161.

    Han, S. et al. Molecular mechanism of type I collagen homotrimer resistance to mammalian collagenases. J. Biol. Chem. 285, 22276–22281 (2010).

    CAS  Google Scholar 

  162. 162.

    Li, L. P., Herzog, W., Korhonen, R. K. & Jurvelin, J. S. The role of viscoelasticity of collagen fibers in articular cartilage: axial tension versus compression. Med. Eng. Phys. 27, 51–57 (2005).

    Google Scholar 

  163. 163.

    Aryaei, A., Vapniarsky, N., Hu, J. C. & Athanasiou, K. A. Recent tissue engineering advances for the treatment of temporomandibular joint disorders. Curr. Osteoporos. Rep. 14, 269–279 (2016).

    Google Scholar 

  164. 164.

    Bozec, L., van der Heijden, G. & Horton, M. Collagen fibrils: nanoscale ropes. Biophys. J. 92, 70–75 (2007).

    CAS  Google Scholar 

  165. 165.

    Orgel, J. P. R. O., San Antonio, J. D. & Antipova, O. Molecular and structural mapping of collagen fibril interactions. Connect. Tissue Res. 52, 2–17 (2011).

    CAS  Google Scholar 

  166. 166.

    Holmes, D. F. & Kadler, K. E. The 10+4 microfibril structure of thin cartilage fibrils. Proc. Natl Acad. Sci. USA 103, 17249–17254 (2006).

    CAS  Google Scholar 

  167. 167.

    Gottardi, R. et al. Supramolecular organization of collagen fibrils in healthy and osteoarthritic human knee and hip joint cartilage. PLoS ONE 11, e0163552 (2016).

    Google Scholar 

  168. 168.

    Eryilmaz, E., Teizer, W. & Hwang, W. In vitro analysis of the co-assembly of type-I and type-III collagen. Cell. Mol. Bioeng. 10, 41–53 (2017).

    CAS  Google Scholar 

  169. 169.

    Gelse, K., Pöschl, E. & Aigner, T. Collagens—structure, function, and biosynthesis. Adv. Drug Deliv. Rev. 55, 1531–1546 (2003).

    CAS  Google Scholar 

  170. 170.

    Petersen, W. & Tillmann, B. Collagenous fibril texture of the human knee joint menisci. Anat. Embryol. 197, 317–324 (1998).

    CAS  Google Scholar 

  171. 171.

    Inoue, H. & Takeda, T. Three-dimensional observation of collagen framework of lumbar intervertebral discs. Acta Orthop. Scand. 46, 949–956 (1975).

    CAS  Google Scholar 

  172. 172.

    Hickey, D. S. & Hukins, D. W. Collagen fibril diameters and elastic fibres in the annulus fibrosus of human fetal intervertebral disc. J. Anat. 133, 351–357 (1981).

    CAS  Google Scholar 

  173. 173.

    Armiento, A. R., Alini, M. & Stoddart, M. J. Articular fibrocartilage - Why does hyaline cartilage fail to repair? Adv. Drug Deliv. Rev. 146, 289–305 (2019).

    CAS  Google Scholar 

  174. 174.

    Karuppal, R. Current concepts in the articular cartilage repair and regeneration. J. Orthop. 14, A1–A3 (2017).

    Google Scholar 

  175. 175.

    Zhang, L., Hu, J. & Athanasiou, K. A. The role of tissue engineering in articular cartilage repair and regeneration. Crit. Rev. Biomed. Eng. 37, 1–57 (2009).

    Google Scholar 

  176. 176.

    Han, E., Chen, S. S., Klisch, S. M. & Sah, R. L. Contribution of proteoglycan osmotic swelling pressure to the compressive properties of articular cartilage. Biophys. J. 101, 916–924 (2011).

    CAS  Google Scholar 

  177. 177.

    Grynpas, M. D., Eyre, D. R. & Kirschner, D. A. Collagen type II differs from type I in native molecular packing. Biochim. Biophys. Acta 626, 346–355 (1980).

    CAS  Google Scholar 

  178. 178.

    Liu, X., Wu, H., Byrne, M., Krane, S. & Jaenisch, R. Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc. Natl Acad. Sci. USA 94, 1852–1856 (1997).

    CAS  Google Scholar 

  179. 179.

    Wu, J.-J., Weis, M. A., Kim, L. S. & Eyre, D. R. Type III collagen, a fibril network modifier in articular cartilage. J. Biol. Chem. 285, 18537–18544 (2010).

    CAS  Google Scholar 

  180. 180.

    Birk, D. E., Fitch, J. M., Babiarz, J. P. & Linsenmayer, T. F. Collagen type I and type V are present in the same fibril in the avian corneal stroma. J. Cell Biol. 106, 999–1008 (1988).

    CAS  Google Scholar 

  181. 181.

    Wenstrup, R. J. et al. Type V collagen controls the initiation of collagen fibril assembly. J. Biol. Chem. 279, 53331–53337 (2004).

    CAS  Google Scholar 

  182. 182.

    Sun, M. et al. Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specific Col5a1-null mouse model. J. Cell Sci. 124, 4096–4105 (2011).

    CAS  Google Scholar 

  183. 183.

    Olsen, B. R. Collagen IX. Int. J. Biochem. Cell Biol. 29, 555–558 (1997).

    CAS  Google Scholar 

  184. 184.

    Eyre, D. R., Pietka, T., Weis, M. A. & Wu, J.-J. Covalent cross-linking of the NC1 domain of collagen type IX to collagen type II in cartilage. J. Biol. Chem. 279, 2568–2574 (2004).

    CAS  Google Scholar 

  185. 185.

    Opolka, A. et al. Collagen IX is indispensable for timely maturation of cartilage during fracture repair in mice. Matrix Biol. 26, 85–95 (2007).

    CAS  Google Scholar 

  186. 186.

    Fässler, R. et al. Mice lacking alpha 1 (IX) collagen develop noninflammatory degenerative joint disease. Proc. Natl Acad. Sci. USA 91, 5070–5074 (1994).

    Google Scholar 

  187. 187.

    Oxford, J. T., Doege, K. J., Horton, W. E. Jr & Morris, N. P. Characterization of type II and type XI collagen synthesis by an immortalized rat chondrocyte cell line (IRC) having a low level of type II collagen mRNA expression. Exp. Cell Res. 213, 28–36 (1994).

    CAS  Google Scholar 

  188. 188.

    Wu, J.-J., Weis, M. A., Kim, L. S., Carter, B. G. & Eyre, D. R. Differences in chain usage and cross-linking specificities of cartilage type V/XI collagen isoforms with age and tissue. J. Biol. Chem. 284, 5539–5545 (2009).

    CAS  Google Scholar 

  189. 189.

    Fichard, A., Kleman, J.-P. & Ruggiero, F. Another look at collagen V and XI molecules. Matrix Biol. 14, 515–531 (1995).

    CAS  Google Scholar 

  190. 190.

    Fernandes, R. J., Weis, M., Scott, M. A., Seegmiller, R. E. & Eyre, D. R. Collagen XI chain misassembly in cartilage of the chondrodysplasia (cho) mouse. Matrix Biol. 26, 597–603 (2007).

    CAS  Google Scholar 

  191. 191.

    Chiquet, M., Birk, D. E., Bönnemann, C. G. & Koch, M. Collagen XII: protecting bone and muscle integrity by organizing collagen fibrils. Int. J. Biochem. Cell Biol. 53, 51–54 (2014).

    CAS  Google Scholar 

  192. 192.

    Taylor, D. W. et al. Collagen type XII and versican are present in the early stages of cartilage tissue formation by both redifferentating passaged and primary chondrocytes. Tissue Eng. Part A 21, 683–693 (2015).

    CAS  Google Scholar 

  193. 193.

    Gregory, K. E., Keene, D. R., Tufa, S. F., Lunstrum, G. P. & Morris, N. P. Developmental distribution of collagen type XII in cartilage: association with articular cartilage and the growth plate. J. Bone Miner. Res. 16, 2005–2016 (2001).

    CAS  Google Scholar 

  194. 194.

    Zou, Y. et al. Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum. Mol. Genet. 23, 2339–2352 (2014).

    CAS  Google Scholar 

  195. 195.

    Ansorge, H. L. et al. Type XIV collagen regulates fibrillogenesis: premature collagen fibril growth and tissue dysfunction in null mice. J. Biol. Chem. 284, 8427–8438 (2009). This paper shows a structure–function relationship of collagen type XIV in skin and immature tendons in a mouse knockout. Cartilage mechanics were not tested but may display similar weakening.

    CAS  Google Scholar 

  196. 196.

    Bell, P. A. et al. Analysis of the cartilage proteome from three different mouse models of genetic skeletal diseases reveals common and discrete disease signatures. Biol. Open 2, 802–811 (2013).

    Google Scholar 

  197. 197.

    Kassner, A. et al. Discrete integration of collagen XVI into tissue-specific collagen fibrils or beaded microfibrils. Matrix Biol. 22, 131–143 (2003).

    CAS  Google Scholar 

  198. 198.

    Grässel, S. & Bauer, R. J. Collagen XVI in health and disease. Matrix Biol. 32, 64–73 (2013).

    Google Scholar 

  199. 199.

    Kassner, A. et al. Molecular structure and interaction of recombinant human type XVI collagen. J. Mol. Biol. 339, 835–853 (2004).

    CAS  Google Scholar 

  200. 200.

    Kvist, A. J. et al. The major basement membrane components localize to the chondrocyte pericellular matrix–a cartilage basement membrane equivalent? Matrix Biol. 27, 22–33 (2008).

    CAS  Google Scholar 

  201. 201.

    Foldager, C. B. et al. Collagen type IV and laminin expressions during cartilage repair and in late clinically failed repair tissues from human subjects. Cartilage 7, 52–61 (2016).

    CAS  Google Scholar 

  202. 202.

    Sudhakar, A. et al. Human alpha1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by alpha1beta1 integrin. J. Clin. Invest. 115, 2801–2810 (2005).

    CAS  Google Scholar 

  203. 203.

    Poschl, E. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628 (2004).

    Google Scholar 

  204. 204.

    Pfaff, M. et al. Integrin and Arg-Gly-Asp dependence of cell adhesion to the native and unfolded triple helix of collagen type VI. Exp. Cell Res. 206, 167–176 (1993).

    CAS  Google Scholar 

  205. 205.

    Gara, S. K. et al. Three novel collagen VI chains with high homology to the alpha3 chain. J. Biol. Chem. 283, 10658–10670 (2008).

    CAS  Google Scholar 

  206. 206.

    Zelenski, N. A. et al. Type VI collagen regulates pericellular matrix properties, chondrocyte swelling, and mechanotransduction in mouse articular cartilage. Arthritis Rheumatol. 67, 1286–1294 (2015).

    CAS  Google Scholar 

  207. 207.

    Shen, G. The role of type X collagen in facilitating and regulating endochondral ossification of articular cartilage. Orthod. Craniofac. Res. 8, 11–17 (2005).

    CAS  Google Scholar 

  208. 208.

    Gress, C. J. & Jacenko, O. Growth plate compressions and altered hematopoiesis in collagen X null mice. J. Cell Biol. 149, 983–993 (2000).

    CAS  Google Scholar 

  209. 209.

    Sund, M. et al. Distinct expression of type XIII collagen in neuronal structures and other tissues during mouse development. Matrix Biol. 20, 215–231 (2001).

    CAS  Google Scholar 

  210. 210.

    Ylönen, R. et al. Type XIII collagen strongly affects bone formation in transgenic mice. J. Bone Miner. Res. 20, 1381–1393 (2005).

    Google Scholar 

  211. 211.

    Koch, M. et al. A novel marker of tissue junctions, collagen XXII. J. Biol. Chem. 279, 22514–22521 (2004).

    CAS  Google Scholar 

  212. 212.

    Zwolanek, D. et al. Collagen XXII binds to collagen-binding integrins via the novel motifs GLQGER and GFKGER. Biochem. J. 459, 217–227 (2014).

    CAS  Google Scholar 

  213. 213.

    Charvet, B. et al. Knockdown of col22a1 gene in zebrafish induces a muscular dystrophy by disruption of the myotendinous junction. Development 140, 4602–4613 (2013).

    CAS  Google Scholar 

  214. 214.

    Hjorten, R. et al. Type XXVII collagen at the transition of cartilage to bone during skeletogenesis. Bone 41, 535–542 (2007).

    CAS  Google Scholar 

  215. 215.

    Plumb, D. A. et al. Collagen XXVII organises the pericellular matrix in the growth plate. PLoS ONE 6, e29422 (2011).

    CAS  Google Scholar 

  216. 216.

    Exposito, J.-Y., Valcourt, U., Cluzel, C. & Lethias, C. The fibrillar collagen family. Int. J. Mol. Sci. 11, 407–426 (2010).

    CAS  Google Scholar 

  217. 217.

    Gonzaga-Jauregui, C. et al. Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population. Eur. J. Hum. Genet. 23, 342–346 (2015).

    CAS  Google Scholar 

  218. 218.

    Pfeiffer, E., Vickers, S. M., Frank, E., Grodzinsky, A. J. & Spector, M. The effects of glycosaminoglycan content on the compressive modulus of cartilage engineered in type II collagen scaffolds. Osteoarthr. Cartil. 16, 1237–1244 (2008).

    CAS  Google Scholar 

  219. 219.

    Rieppo, J. et al. Structure-function relationships in enzymatically modified articular cartilage. Cells Tissues Organs 175, 121–132 (2003).

    Google Scholar 

  220. 220.

    Lee, J.-H. & Cho, J.-Y. Proteomics approaches for the studies of bone metabolism. BMB Rep. 47, 141–148 (2014).

    Google Scholar 

  221. 221.

    Sato, N. et al. Proteomic analysis of human tendon and ligament: solubilization and analysis of insoluble extracellular matrix in connective tissues. J. Proteome Res. 15, 4709–4721 (2016).

    CAS  Google Scholar 

  222. 222.

    Deshmukh, A. S. et al. Deep proteomics of mouse skeletal muscle enables quantitation of protein isoforms, metabolic pathways, and transcription factors. Mol. Cell. Proteom. 14, 841–853 (2015).

    CAS  Google Scholar 

  223. 223.

    Hosseininia, S., Önnerfjord, P. & Dahlberg, L. E. Targeted proteomics of hip articular cartilage in OA and fracture patients. J. Orthop. Res. 37, 131–135 (2019).

    CAS  Google Scholar 

  224. 224.

    Merl-Pham, J. et al. Quantitative proteomic profiling of extracellular matrix and site-specific collagen post-translational modifications in an in vitro model of lung fibrosis. Matrix Biol. Plus 1, 100005 (2019).

    Google Scholar 

  225. 225.

    Ko, J. et al. Machine learning to detect signatures of disease in liquid biopsies – a user’s guide. Lab Chip 18, 395–405 (2018).

    CAS  Google Scholar 

  226. 226.

    Saha, S. et al. Automated detection and classification of early AMD biomarkers using deep learning. Sci. Rep. 9, 10990 (2019).

    Google Scholar 

  227. 227.

    Banaei, N. et al. Machine learning algorithms enhance the specificity of cancer biomarker detection using SERS-based immunoassays in microfluidic chips. RSC Adv. 9, 1859–1868 (2019).

    CAS  Google Scholar 

  228. 228.

    Van Camp, G. et al. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am. J. Hum. Genet. 79, 449–457 (2006).

    Google Scholar 

  229. 229.

    Hafez, A. et al. Col11a1 regulates bone microarchitecture during embryonic development. J. Dev. Biol. 3, 158–176 (2015).

    CAS  Google Scholar 

  230. 230.

    Alexopoulos, L. G., Youn, I., Bonaldo, P. & Guilak, F. Developmental and osteoarthritic changes in Col6a1-knockout mice: Biomechanics of type VI collagen in the cartilage pericellular matrix. Arthritis Rheum. 60, 771–779 (2009). This paper describes the structure–function relationship of collagen type VI and cartilage pericellular matrix stiffness.

    CAS  Google Scholar 

  231. 231.

    Bayer, M. L. et al. Release of tensile strain on engineered human tendon tissue disturbs cell adhesions, changes matrix architecture, and induces an inflammatory phenotype. PLoS ONE 9, e86078 (2014).

    Google Scholar 

  232. 232.

    Pu, X. & Oxford, J. T. Proteomic analysis of engineered cartilage. Methods Mol. Biol. 1340, 263–278 (2015). This paper is the first and only proteomics study of engineered tissue that identifies collagen type XIV.

    CAS  Google Scholar 

  233. 233.

    Fawzi-Grancher, S., De Isla, N., Faure, G., Stoltz, J. F. & Muller, S. Optimisation of biochemical condition and substrates in vitro for tissue engineering of ligament. Ann. Biomed. Eng. 34, 1767–1777 (2006).

    Google Scholar 

  234. 234.

    Richardson, S. M. et al. The differentiation of bone marrow mesenchymal stem cells into chondrocyte-like cells on poly-l-lactic acid (PLLA) scaffolds. Biomaterials 27, 4069–4078 (2006).

    CAS  Google Scholar 

  235. 235.

    Kurobe, H. et al. Development of small diameter nanofiber tissue engineered arterial grafts. PLoS ONE 10, e0120328 (2015).

    Google Scholar 

  236. 236.

    Ashjian, P. et al. Noninvasive in situ evaluation of osteogenic differentiation by time-resolved laser-induced fluorescence spectroscopy. Tissue Eng. 10, 411–420 (2004).

    CAS  Google Scholar 

  237. 237.

    Lee, J. K. et al. Tension stimulation drives tissue formation in scaffold-free systems. Nat. Mater. 16, 864–873 (2017).

    CAS  Google Scholar 

  238. 238.

    Kutsuna, T. et al. Noninvasive evaluation of tissue-engineered cartilage with time-resolved laser-induced fluorescence spectroscopy. Tissue Eng. Part C Methods 16, 365–373 (2010).

    CAS  Google Scholar 

  239. 239.

    Bergholt, M. S., Albro, M. B. & Stevens, M. M. Online quantitative monitoring of live cell engineered cartilage growth using diffuse fiber-optic Raman spectroscopy. Biomaterials 140, 128–137 (2017).

    CAS  Google Scholar 

  240. 240.

    Riesle, J., Hollander, A. P., Langer, R., Freed, L. E. & Vunjak-Novakovic, G. Collagen in tissue-engineered cartilage: types, structure, and crosslinks. J. Cell. Biochem. 71, 313–327 (1998).

    CAS  Google Scholar 

  241. 241.

    Murdoch, A. D., Hardingham, T. E., Eyre, D. R. & Fernandes, R. J. The development of a mature collagen network in cartilage from human bone marrow stem cells in Transwell culture. Matrix Biol. 50, 16–26 (2016).

    CAS  Google Scholar 

  242. 242.

    Lee, J. K., Link, J. M., Hu, J. C. Y. & Athanasiou, K. A. The self-assembling process and applications in tissue engineering. Cold Spring Harb. Perspect. Med. 7, a025668 (2017).

    Google Scholar 

  243. 243.

    Ofek, G. et al. Matrix development in self-assembly of articular cartilage. PLoS ONE 3, e2795 (2008).

    Google Scholar 

  244. 244.

    Makris, E. A., Hu, J. C. & Athanasiou, K. A. Hypoxia-induced collagen crosslinking as a mechanism for enhancing mechanical properties of engineered articular cartilage. Osteoarthr. Cartil. 21, 634–641 (2013).

    CAS  Google Scholar 

  245. 245.

    Makris, E. A., Responte, D. J., Paschos, N. K., Hu, J. C. & Athanasiou, K. A. Developing functional musculoskeletal tissues through hypoxia and lysyl oxidase-induced collagen cross-linking. Proc. Natl Acad. Sci. USA 111, E4832–E4841 (2014).

    CAS  Google Scholar 

  246. 246.

    Yan, D. et al. The impact of low levels of collagen IX and pyridinoline on the mechanical properties of in vitro engineered cartilage. Biomaterials 30, 814–821 (2009).

    CAS  Google Scholar 

  247. 247.

    Setiawati, R. & Rahardjo, P. Bone development and growth. Osteogenesis Bone Regeneration 13 https://doi.org/10.5772/intechopen.82452 (2018).

  248. 248.

    Budde, B. et al. Altered integration of matrilin-3 into cartilage extracellular matrix in the absence of collagen IX. Mol. Cell. Biol. 25, 10465–10478 (2005).

    CAS  Google Scholar 

  249. 249.

    Zhang, R.-Z. et al. Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant. J. Biol. Chem. 285, 10005–10015 (2010).

    CAS  Google Scholar 

  250. 250.

    Schmid, T. M. & Linsenmayer, T. F. Immunoelectron microscopy of type X collagen: Supramolecular forms within embryonic chick cartilage. Dev. Biol. 138, 53–62 (1990).

    CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by NIH grant nos. R01DE015038, R01AR071457 and R01AR067821.

Author information

Affiliations

Authors

Contributions

All authors contributed to all aspects of the article.

Corresponding author

Correspondence to Kyriacos A. Athanasiou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bielajew, B.J., Hu, J.C. & Athanasiou, K.A. Collagen: quantification, biomechanics and role of minor subtypes in cartilage. Nat Rev Mater (2020). https://doi.org/10.1038/s41578-020-0213-1

Download citation

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing