Tenogenic modulating insider factor: Systematic assessment on the functions of tenomodulin gene

Abstract

Tenomodulin (TNMD, Tnmd) is a gene highly expressed in tendon known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. This review aims at providing an encompassing overview of this gene and its protein. In addition, its known expression pattern as well as putative signalling pathways will be described. A chronological overview of the discovered functions of this gene in tendon and other tissues and cells is provided as well as its use as a tendon and ligament lineage marker is assessed in detail and discussed. Last, information about the possible connections between TNMD genomic mutations and mRNA expression to various diseases is delivered. Taken together this review offers a solid synopsis on the up-to-date information available about TNMD and aids at directing and focusing the future research to fully uncover the roles and implications of this interesting gene.

Keywords: BRICHOS; Cell differentiation; Chordae tendineae cordis; Eye; Gene marker; Knockout mice; Metabolic syndrome; Obesity; Periodontal ligament; Single nucleotide polymorphism; Tendon; Tendon stem/progenitor cells; Tenomodulin; Vasculature.

Fig. 1

Flow chart of the search strategy and study selection used in this systematic review.

Fig. 2

Schematic representation of the human TNMD gene. White boxes represent 5′ and 3′ UTR sites, while orange boxes represent exons. Abbreviations: ATG, start codon; kb, kilo base; TAA, stop codon.

Fig. 3

A comparison of the deduced amino acid sequences of tenomodulin proteins and structural features of the human TNMD. (A) Predicted amino acid sequences of human (Shukunami et al. 2001, and Yamana et al. 2001), mouse (Brandau et al. 2001, Shukunami et al. 2001, and Yamana et al. 2001), and chick (Shukunami et al. 2006) tenomodulin. The conserved amino acid residues are shaded and gaps were introduced for optimal alignment. Conserved cysteine residues are indicated in bold with an asterisk. The chicken sequence shares 62% homology with the mouse and human orthologs. The conserved amino.GenBank accession numbers for the aligned sequences are as follows: human TNMD, AF234259.1; mouse Tnmd, AF219993.1; chick TNMD, AY156693. (B) Human TNMD protein includes a type II transmembrane domain at the N terminus, a BRICHOS domain (Sanchez-Pulido et al. 2002) and a C-terminal cysteine-rich domain. The TNMD protein contains two N-glycosylation sites within the BRICHOS domain. Abbreviations: C, cysteine; cTnmd; chicken tenomodulin; hTNMD, human tenomodulin; I, isoleucine; K, lysine; mTnmd, mouse tenomodulin; N, asparagine; Q, glutamine; V, valine; TNMD, Tnmd, tenomodulin.

Fig. 4

Summary of putative upstream and downstream factors in Tnmd-related signalling. The figure is based on studies showing mostly correlations, indicated by the question marks, between TNMD expression or function to other genes and not a direct link in a common signalling cascade. Based on Alberton et al. 2012; Alberton et al. 2015; Brent et al. 2005; Docheva et al. 2005; Frolova et al. 2014; Kimura et al. 2008; Kyriakides et al. 1998; Lejard et al. 2011; Liu et al. 2010; Mendias et al. 2008; Miyabara et al. 2014; Murchison et al. 2007; Shukunami et al. 2006. Abbreviations: Egr, early growth response protein; MMP, matrix metalloproteinase; Thbs, thrombospondin; VEGF, vascular endothelial growth factor.

Fig. 5

Current model of the tenogenic cascade and TNMD involvement. TNMD is marked in orange, transcription factors in blue and other genes in black. Based on Alberton et al. 2015; Berasi et al. 2011; Eloy-Trinquet et al. 2009; Havis et al. 2014; Huang et al. 2015; Lee et al. 2015; Liu et al. 2014; Mienaltowski et al. 2013; Pryce et al. 2009; Shen et al. 2013; Tempfer et al. 2009. Abbreviations: Aqp1, aquaporin 1; BMP, bone morphogenetic protein; Col, collagen; COMP, cartilage oligomeric matrix protein; Egr, early growth response protein; Eya, eyes absent transcription factor; FGF, fibroblast growth factor; Htra3, HtrA serine peptidase 3; IFM, interfascicular matrix; Mkx, Mohawk; Sca-1, stem cells antigen-1; Scx, scleraxis; SMA, smooth muscle actin; TGF, transforming growth factor; Thbs, thrombospondin; Tnmd, tenomodulin.

Fig. 6

Research articles published annually including tenomodulin. (A) All articles published on Pubmed covering tenomodulin and its alternative names tendin and myodulin as well as its abbreviations TNMD and TeM. (B) Distribution of the published research on tenomodulin into four main categories. This figure only includes research published in English and full-text research articles.

Fig. 7

Single nucleotide polymorphism (SNPs) and other putative mutations in the TNMD gene locus correlating with various diseases. Orange boxes represent exons, while the thick black lines connecting them are introns. Abbreviations: rs, reference SNP; SNPs, small nucleotide polymorphisms; UTR, untranslated region.

Fig. 8

Schematic summary of TNMD known functions. Abbreviations: mRNA, messenger ribonucleic acid; Tnmd, tenomodulin; VEGF, vascular endothelial growth factor.