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. 1997;17:102–109.

Decrease in fibronectin occurs coincident with the increased expression of its integrin receptor alpha5beta1 in stress-deprived ligaments.

S S AbiEzzi, R A Foulk, F L Harwood, W H Akeson, D Amiel
PMCID: PMC2378094  PMID: 9234981

Abstract

Stress deprivation secondary to immobilization leads to atrophic changes in periarticular soft tissues. The changes in ligaments include a disorganization of collagen and cellular ultrastructure with varied biochemical alterations resulting in a functionally weaker tissue. This study tests the hypothesis that alterations in fibronectin (Fn) and the expression of its integrin receptor alpha5beta1 in ligament fibroblasts accompany the extracellular matrix remodeling which occurs in stress-deprived knee ligaments. The left knees of eighteen New Zealand white rabbits were surgically immobilized in acute flexion. Fibroblasts within three nine week and three twelve week stress-deprived anterior cruciate ligaments (ACLs) and medial collateral ligaments (MCLs) demonstrated markedly increased immunostaining for the beta1 and alpha5 integrin subunits, as compared to fibroblasts in the contralateral unoperated control ligaments. The effects of stress deprivation on the concentration of Fn was measured by competitive ELISA on the remaining twelve rabbits. Decreases in Fn of 54.0 percent and 63.7 percent occurred in the ACL after nine and twelve weeks of stress deprivation when compared to contralateral controls. The MCL had less of a decrease, losing 37.7 percent and 41.7 percent at nine and twelve weeks, respectively. These results suggest an important role for the Fn-specific integrin receptor alpha5beta1 in remodeling stress-deprived periarticular ligamentous tissue, and the importance of maintaining normal stresses on periarticular ligaments to prevent the degradation of extracellular matrix components such as Fn.

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Selected References

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  1. AbiEzzi S. S., Gesink D. S., Schreck P. J., Amiel D., Akeson W. H., Woods V. L., Jr Increased expression of the beta 1, alpha 5, and alpha v integrin adhesion receptor subunits occurs coincident with remodeling of stress-deprived rabbit anterior cruciate and medial collateral ligaments. J Orthop Res. 1995 Jul;13(4):594–601. doi: 10.1002/jor.1100130415. [DOI] [PubMed] [Google Scholar]
  2. Akeson W. H., Amiel D., LaViolette D., Secrist D. The connective tissue response to immobility: an accelerated ageing response? Exp Gerontol. 1968 Dec;3(4):289–301. doi: 10.1016/0531-5565(68)90040-5. [DOI] [PubMed] [Google Scholar]
  3. Akeson W. H., Amiel D., Mechanic G. L., Woo S. L., Harwood F. L., Hamer M. L. Collagen cross-linking alterations in joint contractures: changes in the reducible cross-links in periarticular connective tissue collagen after nine weeks of immobilization. Connect Tissue Res. 1977;5(1):15–19. doi: 10.3109/03008207709152607. [DOI] [PubMed] [Google Scholar]
  4. Akeson W. H., Woo S. L., Amiel D., Coutts R. D., Daniel D. The connective tissue response to immobility: biochemical changes in periarticular connective tissue of the immobilized rabbit knee. Clin Orthop Relat Res. 1973 Jun;(93):356–362. doi: 10.1097/00003086-197306000-00039. [DOI] [PubMed] [Google Scholar]
  5. Akeson W. H., Woo S. L., Amiel D., Matthews J. V. Biomechanical and biochemical changes in the periarticular connective tissue during contracture development in the immobilized rabbit knee. Connect Tissue Res. 1974;2(4):315–323. doi: 10.3109/03008207409152261. [DOI] [PubMed] [Google Scholar]
  6. Akiyama S. K., Yamada S. S., Chen W. T., Yamada K. M. Analysis of fibronectin receptor function with monoclonal antibodies: roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J Cell Biol. 1989 Aug;109(2):863–875. doi: 10.1083/jcb.109.2.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Amiel D., Akeson W. H., Harwood F. L., Frank C. B. Stress deprivation effect on metabolic turnover of the medial collateral ligament collagen. A comparison between nine- and 12-week immobilization. Clin Orthop Relat Res. 1983 Jan-Feb;(172):265–270. [PubMed] [Google Scholar]
  8. Amiel D., Foulk R. A., Harwood F. L., Akeson W. H. Quantitative assessment by competitive ELISA of fibronectin (Fn) in tendons and ligaments. Matrix. 1989;9(6):421–427. doi: 10.1016/s0934-8832(11)80010-7. [DOI] [PubMed] [Google Scholar]
  9. Amiel D., Frank C., Harwood F., Fronek J., Akeson W. Tendons and ligaments: a morphological and biochemical comparison. J Orthop Res. 1984;1(3):257–265. doi: 10.1002/jor.1100010305. [DOI] [PubMed] [Google Scholar]
  10. Amiel D., Woo S. L., Harwood F. L., Akeson W. H. The effect of immobilization on collagen turnover in connective tissue: a biochemical-biomechanical correlation. Acta Orthop Scand. 1982 Jun;53(3):325–332. doi: 10.3109/17453678208992224. [DOI] [PubMed] [Google Scholar]
  11. Benichou C., Wirotius J. M. Articular cartilage atrophy in lower limb amputees. Arthritis Rheum. 1982 Jan;25(1):80–82. doi: 10.1002/art.1780250113. [DOI] [PubMed] [Google Scholar]
  12. Bray B. A. Quantification of tissue fibronectin from terminal villi of placenta. Biochem J. 1985 Mar 15;226(3):811–815. doi: 10.1042/bj2260811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Clark R. A. Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin. J Invest Dermatol. 1990 Jun;94(6 Suppl):128S–134S. doi: 10.1111/1523-1747.ep12876104. [DOI] [PubMed] [Google Scholar]
  14. Clark R. A. Potential roles of fibronectin in cutaneous wound repair. Arch Dermatol. 1988 Feb;124(2):201–206. [PubMed] [Google Scholar]
  15. Darribère T., Guida K., Larjava H., Johnson K. E., Yamada K. M., Thiery J. P., Boucaut J. C. In vivo analyses of integrin beta 1 subunit function in fibronectin matrix assembly. J Cell Biol. 1990 May;110(5):1813–1823. doi: 10.1083/jcb.110.5.1813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fleischmajer R., Dessau W., Timpl R., Krieg T., Luderschmidt C., Wiestner M. Immunofluorescence analysis of collagen, fibronectin, and basement membrane protein in scleroderma skin. J Invest Dermatol. 1980 Sep;75(3):270–274. doi: 10.1111/1523-1747.ep12523538. [DOI] [PubMed] [Google Scholar]
  17. Gamble J. G., Edwards C. C., Max S. R. Enzymatic adaptation in ligaments during immobilization. Am J Sports Med. 1984 May-Jun;12(3):221–228. doi: 10.1177/036354658401200311. [DOI] [PubMed] [Google Scholar]
  18. Gesink D. S., Pacheco H. O., Kuiper S. D., Schreck P. J., Amiel D., Akeson W. H., Woods V. L., Jr Immunohistochemical localization of beta 1-integrins in anterior cruciate and medial collateral ligaments of human and rabbit. J Orthop Res. 1992 Jul;10(4):596–599. doi: 10.1002/jor.1100100415. [DOI] [PubMed] [Google Scholar]
  19. Grinnell F. Fibronectin and wound healing. J Cell Biochem. 1984;26(2):107–116. doi: 10.1002/jcb.240260206. [DOI] [PubMed] [Google Scholar]
  20. Harper J., Amiel D., Harper E. Collagenases from periarticular ligaments and tendon: enzyme levels during the development of joint contracture. Matrix. 1989 Jun;9(3):200–205. doi: 10.1016/s0934-8832(89)80051-4. [DOI] [PubMed] [Google Scholar]
  21. Harper J., Amiel D., Harper E. Inhibitors of collagenase in ligaments and tendons of rabbits immobilized for 4 weeks. Connect Tissue Res. 1992;28(4):257–261. doi: 10.3109/03008209209016819. [DOI] [PubMed] [Google Scholar]
  22. Harwood F. L., Amiel D. Differential metabolic responses of periarticular ligaments and tendon to joint immobilization. J Appl Physiol (1985) 1992 May;72(5):1687–1691. doi: 10.1152/jappl.1992.72.5.1687. [DOI] [PubMed] [Google Scholar]
  23. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  24. Kischer C. W., Hendrix M. J. Fibronectin (FN) in hypertrophic scars and keloids. Cell Tissue Res. 1983;231(1):29–37. doi: 10.1007/BF00215771. [DOI] [PubMed] [Google Scholar]
  25. Klein L., Player J. S., Heiple K. G., Bahniuk E., Goldberg V. M. Isotopic evidence for resorption of soft tissues and bone in immobilized dogs. J Bone Joint Surg Am. 1982 Feb;64(2):225–230. [PubMed] [Google Scholar]
  26. Kurkinen M., Vaheri A., Roberts P. J., Stenman S. Sequential appearance of fibronectin and collagen in experimental granulation tissue. Lab Invest. 1980 Jul;43(1):47–51. [PubMed] [Google Scholar]
  27. Loitz B. J., Zernicke R. F., Vailas A. C., Kody M. H., Meals R. A. Effects of short-term immobilization versus continuous passive motion on the biomechanical and biochemical properties of the rabbit tendon. Clin Orthop Relat Res. 1989 Jul;(244):265–271. [PubMed] [Google Scholar]
  28. Lyon R. M., Akeson W. H., Amiel D., Kitabayashi L. R., Woo S. L. Ultrastructural differences between the cells of the medical collateral and the anterior cruciate ligaments. Clin Orthop Relat Res. 1991 Nov;(272):279–286. [PubMed] [Google Scholar]
  29. McDonald J. A. Extracellular matrix assembly. Annu Rev Cell Biol. 1988;4:183–207. doi: 10.1146/annurev.cb.04.110188.001151. [DOI] [PubMed] [Google Scholar]
  30. Menzel E. J. Fibronektin in der Dupuytren'schen Kontraktur. Handchir Mikrochir Plast Chir. 1984 Sep;16(3):164–167. [PubMed] [Google Scholar]
  31. Nagelschmidt M., Becker D., Bönninghoff N., Engelhardt G. H. Effect of fibronectin therapy and fibronectin deficiency on wound healing: a study in rats. J Trauma. 1987 Nov;27(11):1267–1271. doi: 10.1097/00005373-198711000-00011. [DOI] [PubMed] [Google Scholar]
  32. Newton P. O., Woo S. L., Kitabayashi L. R., Lyon R. M., Anderson D. R., Akeson W. H. Ultrastructural changes in knee ligaments following immobilization. Matrix. 1990 Oct;10(5):314–319. doi: 10.1016/s0934-8832(11)80187-3. [DOI] [PubMed] [Google Scholar]
  33. Noyes F. R. Functional properties of knee ligaments and alterations induced by immobilization: a correlative biomechanical and histological study in primates. Clin Orthop Relat Res. 1977 Mar-Apr;(123):210–242. [PubMed] [Google Scholar]
  34. Noyes F. R., Torvik P. J., Hyde W. B., DeLucas J. L. Biomechanics of ligament failure. II. An analysis of immobilization, exercise, and reconditioning effects in primates. J Bone Joint Surg Am. 1974 Oct;56(7):1406–1418. [PubMed] [Google Scholar]
  35. Pytela R., Pierschbacher M. D., Ginsberg M. H., Plow E. F., Ruoslahti E. Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp--specific adhesion receptors. Science. 1986 Mar 28;231(4745):1559–1562. doi: 10.1126/science.2420006. [DOI] [PubMed] [Google Scholar]
  36. Rennard S. I., Berg R., Martin G. R., Foidart J. M., Robey P. G. Enzyme-linked immunoassay (ELISA) for connective tissue components. Anal Biochem. 1980 May 1;104(1):205–214. doi: 10.1016/0003-2697(80)90300-0. [DOI] [PubMed] [Google Scholar]
  37. Ruoslahti E., Engvall E., Hayman E. G. Fibronectin: current concepts of its structure and functions. Coll Relat Res. 1981;1(1):95–128. doi: 10.1016/s0174-173x(80)80011-2. [DOI] [PubMed] [Google Scholar]
  38. Ruoslahti E. Fibronectin and its receptors. Annu Rev Biochem. 1988;57:375–413. doi: 10.1146/annurev.bi.57.070188.002111. [DOI] [PubMed] [Google Scholar]
  39. Ruoslahti E., Hayman E. G., Pierschbacher M., Engvall E. Fibronectin: purification, immunochemical properties, and biological activities. Methods Enzymol. 1982;82(Pt A):803–831. doi: 10.1016/0076-6879(82)82103-4. [DOI] [PubMed] [Google Scholar]
  40. Savolainen J., Myllylä V., Myllylä R., Vihko V., Vänänen K., Takala T. E. Effects of denervation and immobilization on collagen synthesis in rat skeletal muscle and tendon. Am J Physiol. 1988 Jun;254(6 Pt 2):R897–R902. doi: 10.1152/ajpregu.1988.254.6.R897. [DOI] [PubMed] [Google Scholar]
  41. Scheel G., Rahfoth B., Franke J., Grau P. Acceleration of wound healing by local application of fibronectin. Arch Orthop Trauma Surg. 1991;110(6):284–287. doi: 10.1007/BF00443459. [DOI] [PubMed] [Google Scholar]
  42. Schreck P. J., Kitabayashi L. R., Amiel D., Akeson W. H., Woods V. L., Jr Integrin display increases in the wounded rabbit medial collateral ligament but not the wounded anterior cruciate ligament. J Orthop Res. 1995 Mar;13(2):174–183. doi: 10.1002/jor.1100130205. [DOI] [PubMed] [Google Scholar]
  43. Singer I. I., Scott S., Kawka D. W., Kazazis D. M., Gailit J., Ruoslahti E. Cell surface distribution of fibronectin and vitronectin receptors depends on substrate composition and extracellular matrix accumulation. J Cell Biol. 1988 Jun;106(6):2171–2182. doi: 10.1083/jcb.106.6.2171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tipton C. M., Matthes R. D., Maynard J. A., Carey R. A. The influence of physical activity on ligaments and tendons. Med Sci Sports. 1975 Fall;7(3):165–175. [PubMed] [Google Scholar]
  45. Vogel B. E., Tarone G., Giancotti F. G., Gailit J., Ruoslahti E. A novel fibronectin receptor with an unexpected subunit composition (alpha v beta 1). J Biol Chem. 1990 Apr 15;265(11):5934–5937. [PubMed] [Google Scholar]
  46. Vuento M., Salonen E., Pasanen M., Stenman U. H. Competitive enzyme immunoassay for human plasma fibronectin. J Immunol Methods. 1981;40(1):101–108. doi: 10.1016/0022-1759(81)90085-5. [DOI] [PubMed] [Google Scholar]
  47. Weinacker A., Chen A., Agrez M., Cone R. I., Nishimura S., Wayner E., Pytela R., Sheppard D. Role of the integrin alpha v beta 6 in cell attachment to fibronectin. Heterologous expression of intact and secreted forms of the receptor. J Biol Chem. 1994 Mar 4;269(9):6940–6948. [PubMed] [Google Scholar]
  48. Woo S. L., Gomez M. A., Sites T. J., Newton P. O., Orlando C. A., Akeson W. H. The biomechanical and morphological changes in the medial collateral ligament of the rabbit after immobilization and remobilization. J Bone Joint Surg Am. 1987 Oct;69(8):1200–1211. [PubMed] [Google Scholar]

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