The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.

Keywords: CTHRC1; Wnt signaling; biomarker; bone erosion; cartilage destruction; collagen triple helix repeat containing 1; fibroblast-like synoviocytes; rheumatoid arthritis.

Figure 1

Domain structure of human CTHRC1. The longest CTHRC1 variant encodes a 243 amino acid protein with a 30 amino acid cleavable signal sequence, followed by a short collagen repeat domain consisting of 12 GXY repeats (where G stands for glycine, X for any amino acid and Y for tyrosine). CTHRC1 also contains a globular cysteine-rich (C indicates the positions of individual cysteine residues) domain with structural similarity to C1q. CTHRC1 is glycosylated, and a single potential glycosylation site is indicated with a red arrow. Aminoterminal (N-) and carboxyterminal (-C) ends of the protein are indicated. Numbers specify amino acid positions within the human protein. Created with BioRender.com.

Figure 2

Model for CTHRC1 modulating collagen deposition and vascular repair following injury through the TGF-β signaling pathway. TGF-β is known to stimulate collagen deposition in various cell types by activating receptor-associated SMAD proteins (SMAD2 and SMAD3). Activated SMAD2 and SMAD3 oligomerize with SMAD4. The complex then translocates into the nucleus, where it regulates the expression of TGF-β-responsive genes, including genes encoding collagen I and III, and CTHRC1. Elevated levels of CTHRC1 eventually lead to attenuation of TGF-β signaling by inhibiting SMAD2/3 phosphorylation [36], possibly leading to SMAD2/3 degradation [21]. Created with BioRender.com.

Figure 3

Role and regulation of CTHRC1 in canonical and noncanonical Wnt signaling. Expression of the N-glycosidase DPAGT1 is induced in response to activation of canonical Wnt/β-catenin signaling. DPAGT1 mediates the N-glycosylation of Wnt ligands and of CTHRC1, thereby enhancing protein stability and secretion of CTHRC1. CTHRC1, in turn, attenuates signaling by the canonical Wnt/β-catenin pathway and induces cytoskeletal reorganization and cell movement via activation of noncanonical Wnt/PCP signaling. Secreted CTHRC1 activates the Wnt/PCP pathway by acting as a co-receptor and promoting the formation of the WNT5A/FZD/ROR2 complex. Created with BioRender.com.

Figure 4

Role of synoviocytes in pannus formation and bone erosion in rheumatoid arthritis (A) and (B) activation of fibroblast-like synoviocytes by cytokines (TNF-α and IL-1β) secreted by synovial macrophages. (SMϕ) leads to the acquisition of a hyper-proliferative, hyper-migratory and hypo-apoptotic phenotype that contributes to the formation of a hyperplastic synovium and ultimately leads to bone and cartilage erosion. Activated synoviocytes in the pannus play a central role in the recruitment and stimulation of immune cells, the vascularization of the pannus through activation of angiogenesis, and the promotion of cartilage and bone erosion. Created with BioRender.com.

Figure 5

A model of CTHRC1 action in osteoclast–osteoblast crosstalk is shown, highlighting the effects of some of the key players involved. Membrane-bound and soluble RANKL produced by cells of the osteoblast lineage and by immune cells induces osteoclastogenesis upon binding to the receptor RANK on osteoclast precursors. RANKL action is opposed by the decoy receptor OPG secreted by osteoblasts or osteocytes. The inflammatory bone environment in RA results in increased production of RANKL by immune cells, osteoblastic cells and synovial fibroblasts. This exacerbates osteoclast differentiation and bone erosion. WNT5A binds to ROR2 receptors and activates non-canonical signaling, thereby promoting osteoclast differentiation and bone resorption. Likewise, signals generated by the binding of stromal-cell-produced colony-stimulating factor 1 (CSF-1) to the C-FMS receptor promote osteoclast differentiation and osteoclastogenesis. TGF-β and other factors, including IGF-1 released from the bone matrix during bone resorption, stimulate osteoblastogenesis [81]. CTHRC1 expression and secretion by osteoclasts points to an autoregulatory mechanism promoting osteoblastogenesis for enhanced bone formation [10,11,82,83], potentially by activating noncanonical Wnt signaling through the co-receptor WAIF1/5T4 [15,83]. An alternative model proposed by Jin et al. implicates osteoblast- and osteocyte-secreted CTHRC1 in the negative regulation of osteoclast differentiation through inhibition of RANKL-RANK signaling [84]. Created with BioRender.com.