Tenomodulin, also referred to as tendin, myodulin, Tnmd, or TeM, is a protein encoded by the TNMD (Tnmd) gene and was discovered independently by Brandau and Shukunami in 2001 as a gene sharing high similarity with the already known chondromodulin-1 (Chm1). It is a tendon-specific gene marker known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells (TSPCs) as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. It is highly expressed in tendons, explaining the rationale behind its name and the establishment as being marker gene for tendinous and ligamentous lineages.
Gene and protein structure TNMD belongs to the new family of type II transmembrane glycoproteins. The gene is localized on the X chromosome and accounts for an approximately 1.4 kb transcript and a predicted protein consisting of 317 amino acids. The gene is composed of seven exons. The second exon encodes the transmembrane domain (amino acid position 31-49) and no signal peptide. TNMD contains a putative protease recognition sequence (Arg-Xxx-Xxx-Arg) identified at the position 233-236. Unlike chondromodulin-1, TNMD does not have a processing signal for furin protease. The extracellular part, prior the putative cleavage site, contains a BRICHOS extracellular domain found also in several other unrelated proteins. This domain consists of a homologous sequence of approximately 100 amino acids containing a pair of conserved cysteine residues. It has been suggested that BRICHOS participates in the protein post-translational processing, however the exact function remains unclear. TNMD contains two N-glycosylation sites at position 94 and 180. Protein analyses in eye and periodontal ligament revealed full length TNMD protein as a double band of 40 and 45 kDa. It has been experimentally proven that the 45 kDa band corresponds to glycosylated TNMD, while 40 kDa band is non-glycosylated TNMD. The last exon of TNMD gene encodes the conserved C-terminal cysteine-rich domain, which makes up the part of the protein sharing highest resemblance to chondromodulin-I (77% similarity/66% identity). This domain contains C-terminal hydrophobic tail with eight Cys residues forming four disulphide-bridges, which are well conserved across vertebrate species. A smaller cyclic structure forming by single Cys280-Cys292 disulphide bridge in TNMD has been shown to exert an anti-angiogenic function, while the other three disulphide-bridges are speculated to hold this cyclic structure and C-terminal hydrophobic tail separated from each other to avoid the formation of intramolecular aggregates. In certain tendon tissues such as Achilles tendon and chordae tendineae cordis, 16 kDa cleaved C-terminal part of TNMD was detected in the collagenous extracellular matrix.
Expression pattern TNMD is highly expressed on messenger and protein levels in tendons and ligaments, but has also been found in other tissues. - In tendon development first signals are detectable as early as E9.5, but upregulated from E14.5 onwards, marking the differentiated stage of tendon progenitors. - Mouse periodontal ligaments demonstrated tenomodulin protein expression at 3 and 4 weeks postnatal, a time period corresponding to molar eruptive and post-eruptive phases when the teeth become functional. - Other tendinous tissues known to express Tnmd are the diaphragm and chordae tendineae cordis. - Masseter muscle is compartmentalized by a laminar structure, which was shown to elevate Tnmd mRNA in mouse embryos between E12.5 to E17.5, which further decreased after birth. The epimysium of skeletal muscle is also TNMD -positive. - Tnmd mRNA was detected in eyes, more specifically in the sclerocornea, tendon of the extraocular muscle and the retinal ganglion cell layer, lens fibre cells, inner nuclear layer cells and pigment epithelium. - Tnmd mRNA was detected in mouse skin at E15.5 and in human subcutaneous adipose tissue and adipocytes. - In situ hybridization revealed Tnmd expression in various parts of the adult mouse brain such as the dentate gyrus, CA regions of the hippocampus, neurons in the cerebral nuclei, cerebellum, Purkinje cells and neuronal cells in the cerebellar nucleus. - Rat mandibular condylar cartilage is positive for Tnmd mRNA at 1 week and is downregulated after 5 weeks.
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