Chondromodulin-1 in health, osteoarthritis, cancer, and heart disease

Abstract

The human chondromodulin-1 (Chm-1, Chm-I, CNMD, or Lect1) gene encodes a 334 amino acid type II transmembrane glycoprotein protein with characteristics of a furin cleavage site and a putative glycosylation site. Chm-1 is expressed most predominantly in healthy and developing avascular cartilage, and healthy cardiac valves. Chm-1 plays a vital role during endochondral ossification by the regulation of angiogenesis. The anti-angiogenic and chondrogenic properties of Chm-1 are attributed to its role in tissue development, homeostasis, repair and regeneration, and disease prevention. Chm-1 promotes chondrocyte differentiation, and is regulated by versatile transcription factors, such as Sox9, Sp3, YY1, p300, Pax1, and Nkx3.2. Decreased expression of Chm-1 is implicated in the onset and progression of osteoarthritis and infective endocarditis. Chm-1 appears to attenuate osteoarthritis progression by inhibiting catabolic activity, and to mediate anti-inflammatory effects. In this review, we present the molecular structure and expression profiling of Chm-1. In addition, we bring a summary to the potential role of Chm-1 in cartilage development and homeostasis, osteoarthritis onset and progression, and to the pathogenic role of Chm-1 in infective endocarditis and cancers. To date, knowledge of the Chm-1 receptor, cellular signalling, and the molecular mechanisms of Chm-1 is rudimentary. Advancing our understanding the role of Chm-1 and its mechanisms of action will pave the way for the development of Chm-1 as a therapeutic target for the treatment of diseases, such as osteoarthritis, infective endocarditis, and cancer, and for potential tissue regenerative bioengineering applications.

Keywords: Bone; Embryo; Fertility; Heart; Immune; Tumour.

Fig. 1

Multiple sequence alignment showing substantial identity among Chm-1 amino acid sequences in human, mouse, rat, bovine, and rabbit, with a consensus potential glycosylation site underlined, and a putative furin cleavage site (RERR) in bold font (a). Multiple sequence alignment showing limited homology between human Chm-1 (LECT1) and chondromodulin-II (LECT2) amino acid sequence at their C-terminal regions (b)

Fig. 2

Molecular structure of Chm-1. Secondary structure of Chm-1 showing that it contains a transmembrane domain between amino acid residues 40–65, a furin cleavage site (RERR) at 215 amino acid residue, an N-linked glycosylation site (NET) at 243 amino acid residue, and a BRICHOS domain from 104–210 amino acid residues (a). Tertiary structure analysis reveals that it features a typical helical conformation based on the Phyre2 web portal for protein modelling (http://twitter.com/phyre2server) (b), and by RaptorX template-based protein structure modelling (http://raptorx.uchicago.edu/StructurePrediction) (c)

Fig. 3

Expression analyses showing the Chm-1 expression in both human (a) and mouse (b) tissues, with 10 most highly expressed tissues for each species, performed by Genevisible^® (http://genevisible.com)

Fig. 4

Expression analyses showing the Chm-1 expression in both human (a) and mouse (b) cell lines, with 10 most highly expressed cell lines for each species, performed by Genevisible^® (http://genevisible.com)

Fig. 5

A hypothetical working model of Chm-1. a Chm-1 gene is expressed by many cell types and tissues such as avascular cartilage cells, cardiac valves, growth plate, foetal retina pigment epithelium cells, embryo tissue, ovarian granulosa cells, embryonic vertebrae, and stria vascularis tissues. Its expression is regulated by transcription factors including Sox9, Sp3, YY1, p300, Pax1, and Nkx3.2. b Precursor Chm-1, as a type II transmembrane glycoprotein protein is cleaved by furin to release its mature Chm-1. Mature Chm-1 binds to an unknown receptor in a cell type dependent manner and mediates downstream signalling cascades such as GRP78-PI3K-AKT and mTOR signalling for cell survival, Stat signalling for tumour cell suppression, and HIF-2α signalling for angiogenesis and chondrogenesis