Tenomodulin Is Necessary for Tenocyte Proliferation and Tendon Maturation

Abstract

Tenomodulin (Tnmd) is a member of a new family of type II transmembrane glycoproteins. It is predominantly expressed in tendons, ligaments, and eyes, whereas the only other family member, chondromodulin I (ChM-I), is highly expressed in cartilage and at lower levels in the eye and thymus. The C-terminal extracellular domains of both proteins were shown to modulate endothelial-cell proliferation and tube formation in vitro and in vivo. We analyzed Tnmd function in vivo and provide evidence that Tnmd is processed in vivo and that the proteolytically cleaved C-terminal domain can be found in tendon extracts. Loss of Tnmd expression in gene targeted mice abated tenocyte proliferation and led to a reduced tenocyte density. The deposited amounts of extracellular matrix proteins, including collagen types I, II, III, and VI and decorin, lumican, aggrecan, and matrilin-2, were not affected, but the calibers of collagen fibrils varied significantly and exhibited increased maximal diameters. Tnmd-deficient mice did not have changes in tendon vessel density, and mice lacking both Tnmd and ChM-I had normal retinal vascularization and neovascularization after oxygen-induced retinopathy. These results suggest that Tnmd is a regulator of tenocyte proliferation and is involved in collagen fibril maturation but do not confirm an in vivo involvement of Tnmd in angiogenesis.

ACKNOWLEDGMENTS

We thank Edward Fellows for reading the manuscript, Attila Aszódi for helpful suggestions, and Nikola Popov for supervision and administrative support at the University of Plovdiv, Plovdiv, Bulgaria. We are indebted to Rupert Timpl, Takako Sasaki, Richard Holmdahl, Åke Oldberg, Dietmar Vestweber, and Raimund Wagener for providing antibodies.

R.F. is supported by the Fonds der Chemischen Industrie and the Max Planck Society.