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 oxygeninduced 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.Tendons and ligaments connect the elements of the musculoskeletal system and are composed of a densely packed collagen-rich connective tissue able to withstand high tensile forces. Collagen type I is predominant, but collagen types III,

Scleraxis is Required for Differentiation of the Stapedius and Tensor Tympani Tendons of the Middle Ear

“…Moreover, direct regulation of collagen I enhancers has been demonstrated (Lejard et al 2007;Espira et al 2009). Collagen XIV regulates the diameter of collagen fibrils (Young et al 2002), tenomodulin subtly influences tendon proliferation (Docheva et al 2005), and collagen I is the major structural protein in the collagen matrix of tendons (Orgel et al 2006). The misregulation of these proteins in Scx-nulls is not thought to account for Scx function in tenocyte differentiation and for the range of phenotypes observed in the tendons of mutants .…”

A Prospectus of Tenomodulin

“…BD has been supposed to have a chaperone function 9 , but the functional role of BD remains totally unclear. Both proteins have a secreted part -16 kDa for TNMD 6 and 25 kDa for pre-ChM-I. 15,16 Recent data demonstrates that TNMD and preChM-I are able to release their CTDs in vitro and in vivo.…”

“…A lot of studies confi rmed its important role in the tendon differentiation 4,6 and in the inhibition of angiogenesis 5,7 . Tenomodulin regulates various biological processes, but most of its functional mechanisms are still unknown.…”

In VitroEvaluation of a Novel Non-Mulberry Silk Scaffold for Use in Tendon Regeneration

“…These included fibromodulin, an extracellular matrix protein important for the tendon stem cell niche, 46 scleraxis, a key transcription factor required for tenocyte development, 48,49 and tenomodullin, which is necessary for tenocyte proliferation. 50 Commitment of progenitors to the tenocyte lineage and subsequent tenocyte proliferation and FIG. 8.…”

“…45 Genes assayed were biglycan (Rn01529734_g1) and fibromodulin (Rn00589918_m1), extracellular matrix proteins important in maintaining a tendon stem cell niche 46 ; collagen type I (Rn00673737_m1), the main structural collagen present in tendon 1 ; tenascin C (Rn01454947_m1), a glycoprotein important during the development and repair of tendons 47 ; scleraxis (Rn01504576_m1), a key transcription factor in tenocyte differentiation 48,49 ; and tenomodulin (Rn00574164_m1), a key glycoprotein in the proliferation and development of tenocytes. 50 Chondrocyte and osteoblast genes were also assessed as tenocytes tend to transdifferentiate into such cell types, one of the pathological causes of tendinopathy. 51 The assessed genes were collagen type II (Rn01637087_m1), the major structural collagen of cartilage 52 ; aggrecan (Rn00573424_m1), the major glycoprotein in cartilage and a marker of chondrogenesis 53 ; Sp7 (osterix) (Rn02769744_s1), a transcription factor and marker of osteoblast differentiation 54 ; and bone sialoprotein (Rn00561414_m1), a marker of late osteoblast differentiation.…”