Research Article
No access
Published Online: 9 November 2011

Spatial and Temporal Expression of Molecular Markers and Cell Signals During Normal Development of the Mouse Patellar Tendon

Publication: Tissue Engineering Part A
Volume 18, Issue Number 5-6

Abstract

Tendon injuries are common clinical problems and are difficult to treat. In particular, the tendon-to-bone insertion site, once damaged, does not regenerate its complex zonal arrangement. A potential treatment for tendon injuries is to replace injured tendons with bioengineered tendons. However, the bioengineering of tendon will require a detailed understanding of the normal development of tendon, which is currently lacking. Here, we use the mouse patellar tendon as a model to describe the spatial and temporal pattern of expression of molecular markers for tendon differentiation from late fetal life to 2 weeks after birth. We found that collagen I, fibromodulin, and tenomodulin were expressed throughout the tendon, whereas tenascin-C, biglycan, and cartilage oligomeric protein were concentrated in the insertion site during this period. We also identified signaling pathways that are activated both throughout the developing tendon, for example, transforming growth factor beta and bone morphogenetic protein, and specifically in the insertion site, for example, hedgehog pathway. Using a mouse line expressing green fluorescent protein in all tenocytes, we also found that tenocyte cell proliferation occurs at highest levels during late fetal life, and declines to very low levels by 2 weeks after birth. These data will allow both the functional analysis of specific signaling pathways in tenocyte development and their application to tissue-engineering studies in vitro.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Klepps S.Bishop J.Lin J.Cahlon O.Strauss A.Hayes P. et al. Prospective evaluation of the effect of rotator cuff integrity on the outcome of open rotator cuff repairsAm J Sports Med3217162004. 1. Klepps, S., Bishop, J., Lin, J., Cahlon, O., Strauss, A., Hayes, P., et al. Prospective evaluation of the effect of rotator cuff integrity on the outcome of open rotator cuff repairs. Am J Sports Med 32, 1716, 2004.
2.
Jost B.Pfirrmann C.W.Gerber C.Switzerland Z. Clinical outcome after structural failure of rotator cuff repairsJ Bone Joint Surg Am823042000. 2. Jost, B., Pfirrmann, C.W., Gerber, C., and Switzerland, Z. Clinical outcome after structural failure of rotator cuff repairs. J Bone Joint Surg Am 82, 304, 2000.
3.
Praemer A.Furner S.Rice D.Musculoskeletal Condition in the United StatesParke Ridge, ILAmerican Academy of Orthopaedic Surgeons1999. 3. Praemer, A., Furner, S., and Rice, D. Musculoskeletal Condition in the United States. Parke Ridge, IL: American Academy of Orthopaedic Surgeons, 1999.
4.
Sharma P.Maffulli N. Tendon injury and tendinopathy: healing and repairJ Bone Joint Surg Am871872005. 4. Sharma, P., and Maffulli, N. Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am 87, 187, 2005.
5.
Riley G. Tendinopathy—from basic science to treatmentNat Clin Pract Rheumatol4822008. 5. Riley, G. Tendinopathy—from basic science to treatment. Nat Clin Pract Rheumatol 4, 82, 2008.
6.
Austin J.C.Phornphutkul C.Wojtys E.M. Loss of knee extension after anterior cruciate ligament reconstruction: effects of knee position and graft tensioningJ Bone Joint Surg Am8915652007. 6. Austin, J.C., Phornphutkul, C., and Wojtys, E.M. Loss of knee extension after anterior cruciate ligament reconstruction: effects of knee position and graft tensioning. J Bone Joint Surg Am 89, 1565, 2007.
7.
Petsche T.S.Hutchinson M.R. Loss of extension after reconstruction of the anterior cruciate ligamentJ Am Acad Orthop Surg71191999. 7. Petsche, T.S., and Hutchinson, M.R. Loss of extension after reconstruction of the anterior cruciate ligament. J Am Acad Orthop Surg 7, 119, 1999.
8.
Juncosa N.West J.R.Galloway M.T.Boivin G.P.Butler D.L. In vivo forces used to develop design parameters for tissue engineered implants for rabbit patellar tendon repairJ Biomech364832003. 8. Juncosa, N., West, J.R., Galloway, M.T., Boivin, G.P., and Butler, D.L. In vivo forces used to develop design parameters for tissue engineered implants for rabbit patellar tendon repair. J Biomech 36, 483, 2003.
9.
Butler D.L.Juncosa-Melvin N.Boivin G.P.Galloway M.T.Shearn J.T.Gooch C. et al. Functional tissue engineering for tendon repair: a multidisciplinary strategy using mesenchymal stem cells, bioscaffolds, and mechanical stimulationJ Orthop Res2612008. 9. Butler, D.L., Juncosa-Melvin, N., Boivin, G.P., Galloway, M.T., Shearn, J.T., Gooch, C., et al. Functional tissue engineering for tendon repair: a multidisciplinary strategy using mesenchymal stem cells, bioscaffolds, and mechanical stimulation. J Orthop Res 26, 1, 2008.
10.
Juncosa-Melvin N.Matlin K.S.Holdcraft R.W.Nirmalanandhan V.S.Butler D.L. Mechanical stimulation increases collagen type I and collagen type III gene expression of stem cell-collagen sponge constructs for patellar tendon repairTissue Eng1312192007. 10. Juncosa-Melvin, N., Matlin, K.S., Holdcraft, R.W., Nirmalanandhan, V.S., and Butler, D.L. Mechanical stimulation increases collagen type I and collagen type III gene expression of stem cell-collagen sponge constructs for patellar tendon repair. Tissue Eng 13, 1219, 2007.
11.
Kahane N.Cinnamon Y.Bachelet I.Kalcheim C. The third wave of myotome colonization by mitotically competent progenitors: regulating the balance between differentiation and proliferation during muscle developmentDevelopment12821872001. 11. Kahane, N., Cinnamon, Y., Bachelet, I., and Kalcheim, C. The third wave of myotome colonization by mitotically competent progenitors: regulating the balance between differentiation and proliferation during muscle development. Development 128, 2187, 2001.
12.
Brent A.E.Schweitzer R.Tabin C.J. A somitic compartment of tendon progenitorsCell1132352003. 12. Brent, A.E., Schweitzer, R., and Tabin, C.J. A somitic compartment of tendon progenitors. Cell 113, 235, 2003.
13.
Brent A.E.Tabin C.J. FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expressionDevelopment13138852004. 13. Brent, A.E., and Tabin, C.J. FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression. Development 131, 3885, 2004.
14.
Schweitzer R.Chyung J.H.Murtaugh L.C.Brent A.E.Rosen V.Olson E.N. et al. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligamentsDevelopment12838552001. 14. Schweitzer, R., Chyung, J.H., Murtaugh, L.C., Brent, A.E., Rosen, V., Olson, E.N., et al. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 128, 3855, 2001.
15.
Edom-Vovard F.Bonnin M.Duprez D. Fgf8 transcripts are located in tendons during embryonic chick limb developmentMech Dev1082032001. 15. Edom-Vovard, F., Bonnin, M., and Duprez, D. Fgf8 transcripts are located in tendons during embryonic chick limb development. Mech Dev 108, 203, 2001.
16.
Pryce B.A.Watson S.S.Murchison N.D.Staverosky J.A.Dünker N.Schweitzer R. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formationDevelopment13613512009. 16. Pryce, B.A., Watson, S.S., Murchison, N.D., Staverosky, J.A., Dünker, N., and Schweitzer, R. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation. Development 136, 1351, 2009.
17.
Brown D.Wagner D.Li X.Richardson J.A.Olson E.N. Dual role of the basic helix-loop-helix transcription factor scleraxis in mesoderm formation and chondrogenesis during mouse embryogenesisDevelopment12643171999. 17. Brown, D., Wagner, D., Li, X., Richardson, J.A., and Olson, E.N. Dual role of the basic helix-loop-helix transcription factor scleraxis in mesoderm formation and chondrogenesis during mouse embryogenesis. Development 126, 4317, 1999.
18.
Ito Y.Toriuchi N.Yoshitaka T.Ueno-Kudoh H.Sato T.Yokoyama S. et al. The Mohawk homeobox gene is a critical regulator of tendon differentiationProc Natl Acad Sci USA107105382010. 18. Ito, Y., Toriuchi, N., Yoshitaka, T., Ueno-Kudoh, H., Sato, T., Yokoyama, S., et al. The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc Natl Acad Sci USA 107, 10538, 2010.
19.
Blitz E.Viukov S.Sharir A.Shwartz Y.Galloway J.L.Pryce B.A. et al. Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junctionDev Cell178612009. 19. Blitz, E., Viukov, S., Sharir, A., Shwartz, Y., Galloway, J.L., Pryce, B.A., et al. Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junction. Dev Cell 17, 861, 2009.
20.
Pryce B.A.Brent A.E.Murchison N.D.Tabin C.J.Schweitzer R. Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis geneDev Dyn23616772007. 20. Pryce, B.A., Brent, A.E., Murchison, N.D., Tabin, C.J., and Schweitzer, R. Generation of transgenic tendon reporters, ScxGFP and ScxAP, using regulatory elements of the scleraxis gene. Dev Dyn 236, 1677, 2007.
21.
Lillie R.D.Histopathologic Technic and Practical Histochemistry3rdNew YorkMcGraw-Hill Book Co1965. 21. Lillie, R.D. Histopathologic Technic and Practical Histochemistry, 3rd edition. New York: McGraw-Hill Book Co, 1965.
22.
DasGupta R.Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiationDevelopment12645571999. 22. DasGupta, R., and Fuchs, E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557, 1999.
23.
Bai C.B.Auerbach W.Lee J.S.Stephen D.Joyner A.L. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathwayDevelopment12947532002. 23. Bai, C.B., Auerbach, W., Lee, J.S., Stephen, D., and Joyner, A.L. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129, 4753, 2002.
24.
Liu S.H.Yang R.S.al-Shaikh R.Lane J.M. Collagen in tendon, ligament, and bone healing. A current reviewClin Orthop Relat Res3182651995. 24. Liu, S.H., Yang, R.S., al-Shaikh, R., and Lane, J.M. Collagen in tendon, ligament, and bone healing. A current review. Clin Orthop Relat Res 318, 265, 1995.
25.
Docheva D.Hunziker E.B.Fassler R.Brandau O. Tenomodulin is necessary for tenocyte proliferation and tendon maturationMol Cell Biol256992005. 25. Docheva, D., Hunziker, E.B., Fassler, R., and Brandau, O. Tenomodulin is necessary for tenocyte proliferation and tendon maturation. Mol Cell Biol 25, 699, 2005.
26.
Hedlund H.Mengarelli-Widholm S.Heinegard D.Reinholt F.P.Svensson O. Fibromodulin distribution and association with collagenMatrix Biol142271994. 26. Hedlund, H., Mengarelli-Widholm, S., Heinegard, D., Reinholt, F.P., and Svensson, O. Fibromodulin distribution and association with collagen. Matrix Biol 14, 227, 1994.
27.
Svensson L.Aszodi A.Reinholt F.P.Fassler R.Heinegard D.Oldberg A. Fibromodulin-null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendonJ Biol Chem27496361999. 27. Svensson, L., Aszodi, A., Reinholt, F.P., Fassler, R., Heinegard, D., and Oldberg, A. Fibromodulin-null mice have abnormal collagen fibrils, tissue organization, and altered lumican deposition in tendon. J Biol Chem 274, 9636, 1999.
28.
Riley G. The pathogenesis of tendinopathy. A molecular perspectiveRheumatology (Oxford)431312004. 28. Riley, G. The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford) 43, 131, 2004.
29.
DiCesare P.Hauser N.Lehman D.Pasumarti S.Paulsson M. Cartilage oligomeric matrix protein (COMP) is an abundant component of tendonFEBS Lett3542371994. 29. DiCesare, P., Hauser, N., Lehman, D., Pasumarti, S., and Paulsson, M. Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon. FEBS Lett 354, 237, 1994.
30.
Pajala A.Melkko J.Leppilahti J.Ohtonen P.Soini Y.Risteli J. Tenascin-C and type I and III collagen expression in total Achilles tendon rupture. An immunohistochemical studyHistol Histopathol2412072009. 30. Pajala, A., Melkko, J., Leppilahti, J., Ohtonen, P., Soini, Y., and Risteli, J. Tenascin-C and type I and III collagen expression in total Achilles tendon rupture. An immunohistochemical study. Histol Histopathol 24, 1207, 2009.
31.
Riley G.P.Harrall R.L.Cawston T.E.Hazleman B.L.Mackie E.J. Tenascin-C and human tendon degenerationAm J Pathol1499331996. 31. Riley, G.P., Harrall, R.L., Cawston, T.E., Hazleman, B.L., and Mackie, E.J. Tenascin-C and human tendon degeneration. Am J Pathol 149, 933, 1996.
32.
Wurgler-Hauri C.C.Dourte L.M.Baradet T.C.Williams G.R.Soslowsky L.J. Temporal expression of 8 growth factors in tendon-to-bone healing in a rat supraspinatus modelJ Shoulder Elbow Surg16S1982007. 32. Wurgler-Hauri, C.C., Dourte, L.M., Baradet, T.C., Williams, G.R., and Soslowsky, L.J. Temporal expression of 8 growth factors in tendon-to-bone healing in a rat supraspinatus model. J Shoulder Elbow Surg 16, S198, 2007.
33.
Garcion E.Halilagic A.Faissner A.ffrench-Constant C. Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin CDevelopment13134232004. 33. Garcion, E., Halilagic, A., Faissner, A., and ffrench-Constant, C. Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. Development 131, 3423, 2004.
34.
Bi Y.Ehirchiou D.Kilts T.M.Inkson C.A.Embree M.C.Sonoyama W.F. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their nicheNat Med1312192007. 34. Bi, Y., Ehirchiou, D., Kilts, T.M., Inkson, C.A., Embree, M.C., Sonoyama, W., F. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 13, 1219, 2007.
35.
Thomopoulos S.Genin G.M.Galatz L.M. The development and morphogenesis of the tendon-to-bone insertion - what development can teach us about healingJ Musculoskelet Neuronal Interact10352010. 35. Thomopoulos, S., Genin, G.M., and Galatz, L.M. The development and morphogenesis of the tendon-to-bone insertion - what development can teach us about healing. J Musculoskelet Neuronal Interact 10, 35, 2010.
36.
Mak K.K.Kronenberg H.M.Chuang P.T.Mackem S.Yang Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophyDevelopment13519472008. 36. Mak, K.K., Kronenberg, H.M., Chuang, P.T., Mackem, S., and Yang, Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135, 1947, 2008.
37.
Nie X.Luukko K.Kvinnsland I.H.Kettunen P. Developmentally regulated expression of Shh and Ihh in the developing mouse cranial base: comparison with Sox9 expressionAnat Rec A Discov Mol Cell Evol Biol2868912005. 37. Nie, X., Luukko, K., Kvinnsland, I.H., and Kettunen, P. Developmentally regulated expression of Shh and Ihh in the developing mouse cranial base: comparison with Sox9 expression. Anat Rec A Discov Mol Cell Evol Biol 286, 891, 2005.
38.
Yoon J.H.Halper J. Tendon proteoglycans: biochemistry and functionJ o Musculoskelet Neuronal Interact5222005. 38. Yoon, J.H., and Halper, J. Tendon proteoglycans: biochemistry and function. J o Musculoskelet Neuronal Interact 5, 22, 2005.
39.
Mullor J.L.Sanchez P.Ruiz IAltaba A. Pathways and consequences: Hedgehog signaling in human diseaseTrends Cell Biol125622002. 39. Mullor, J.L., Sanchez, P., and Ruiz I Altaba, A. Pathways and consequences: Hedgehog signaling in human disease. Trends Cell Biol 12, 562, 2002.
40.
Liu C.F.Aschbacher-Smith L.Barthelery N.J.Dyment N.Butler D.Wylie C. What we should know before using tissue engineering techniques to repair injured tendons: a developmental biology perspectiveTissue Eng Part B Rev171652011. 40. Liu, C.F., Aschbacher-Smith, L., Barthelery, N.J., Dyment, N., Butler, D., and Wylie, C. What we should know before using tissue engineering techniques to repair injured tendons: a developmental biology perspective. Tissue Eng Part B Rev 17, 165, 2011.
41.
Edom-Vovard F.Schuler B.Bonnin M.A.Teillet M.A.Duprez D. Fgf4 positively regulates scleraxis and tenascin expression in chick limb tendonsDev Biol2473512002. 41. Edom-Vovard, F., Schuler, B., Bonnin, M.A., Teillet, M.A., and Duprez, D. Fgf4 positively regulates scleraxis and tenascin expression in chick limb tendons. Dev Biol 247, 351, 2002.
42.
Chan K.M.Fu S.C.Wong Y.P.Hui W.C.Cheuk Y.C.Wong M.W. Expression of transforming growth factor beta isoforms and their roles in tendon healingWound Repair Regen163992008. 42. Chan, K.M., Fu, S.C., Wong, Y.P., Hui, W.C., Cheuk, Y.C., and Wong, M.W. Expression of transforming growth factor beta isoforms and their roles in tendon healing. Wound Repair Regen 16, 399, 2008.
43.
Fukui N.Katsuragawa Y.Sakai H.Oda H.Nakamura K. Effect of local application of basic fibroblast growth factor on ligament healing in rabbitsRev Rhum Engl Ed654061998. 43. Fukui, N., Katsuragawa, Y., Sakai, H., Oda, H., and Nakamura, K. Effect of local application of basic fibroblast growth factor on ligament healing in rabbits. Rev Rhum Engl Ed 65, 406, 1998.
44.
Kobayashi D.Kurosaka M.Yoshiya S.Mizuno K. Effect of basic fibroblast growth factor on the healing of defects in the canine anterior cruciate ligamentKnee Surg Sports Traumatol Arthrosc51891997. 44. Kobayashi, D., Kurosaka, M., Yoshiya, S., and Mizuno, K. Effect of basic fibroblast growth factor on the healing of defects in the canine anterior cruciate ligament. Knee Surg Sports Traumatol Arthrosc 5, 189, 1997.
45.
Jones M.E.Mudera V.Brown R.A.Cambrey A.D.Grobbelaar A.O.McGrouther D.A. The early surface cell response to flexor tendon injuryJ Hand Surg Am282212003. 45. Jones, M.E., Mudera, V., Brown, R.A., Cambrey, A.D., Grobbelaar, A.O., and McGrouther, D.A. The early surface cell response to flexor tendon injury. J Hand Surg Am 28, 221, 2003.
46.
Gelberman R.H.Manske P.R.Vande Berg J.S.Lesker P.A.Akeson W.H. Flexor tendon repair in vitro: a comparative histologic study of the rabbit, chicken, dog, and monkeyJ Orthop Res2391984. 46. Gelberman, R.H., Manske, P.R., Vande Berg, J.S., Lesker, P.A., and Akeson, W.H. Flexor tendon repair in vitro: a comparative histologic study of the rabbit, chicken, dog, and monkey. J Orthop Res 2, 39, 1984.
47.
Hatano I.Suga T.Diao E.Peimer C.A.Howard C. Adhesions from flexor tendon surgery: an animal study comparing surgical techniquesJ Hand Surg Am252522000. 47. Hatano, I., Suga, T., Diao, E., Peimer, C.A., and Howard, C. Adhesions from flexor tendon surgery: an animal study comparing surgical techniques. J Hand Surg Am 25, 252, 2000.

Information & Authors

Information

Published In

cover image Tissue Engineering Part A
Tissue Engineering Part A
Volume 18Issue Number 5-6March 2012
Pages: 598 - 608
PubMed: 21939397

History

Published in print: March 2012
Published online: 9 November 2011
Published ahead of production: 22 September 2011
Accepted: 21 September 2011
Received: 15 June 2011

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Chia-Feng Liu
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio.
Lindsey Aschbacher-Smith
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio.
Nicolas J. Barthelery
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio.
Nathaniel Dyment
Biomedical Engineering Program, School of Energy, Environment, and Biological and Medical Engineering, University of Cincinnati, Cincinnati, Ohio.
David Butler
Biomedical Engineering Program, School of Energy, Environment, and Biological and Medical Engineering, University of Cincinnati, Cincinnati, Ohio.
Christopher Wylie
Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio.

Notes

Address correspondence to:Christopher Wylie, Ph.D.Division of Developmental BiologyCincinnati Children's Hospital Research Foundation3333 Burnet Ave.Cincinnati, OH 45229E-mail: [email protected]

Disclosure Statement

No competing financial interests exist.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/EPUB

Full Text

View Full Text

Figures

Tables

Media

Share

Share

Copy the content Link

Share on social media

Back to Top