WAIF1 Is a Cell-Surface CTHRC1 Binding Protein Coupling Bone Resorption and Formation

Abstract

The osteoclast-derived collagen triple helix repeat containing 1 (CTHRC1) protein stimulates osteoblast differentiation, but the underlying mechanism remains unclear. Here, we identified Wnt-activated inhibitory factor 1 (WAIF1)/5T4 as a cell-surface protein binding CTHRC1. The WAIF1-encoding Trophoblast glycoprotein (Tpbg) gene, which is abundantly expressed in the brain and bone but not in other tissues, showed the same expression pattern as Cthrc1. Tpbg downregulation in marrow stromal cells reduced CTHRC1 binding and CTHRC1-stimulated alkaline phosphatase activity through PKCδ activation of MEK/ERK, suggesting a novel WAIF1/PKCδ/ERK pathway triggered by CTHRC1. Unexpectedly, osteoblast lineage-specific deletion of Tpbg downregulated Rankl expression in mouse bones and reduced both bone formation and resorption; importantly, it impaired bone mass recovery following RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency. Thus, the binding of osteoclast-derived CTHRC1 to WAIF1 in stromal cells activates PKCδ-ERK osteoblastogenic signaling and serves as a key molecular link between bone resorption and formation during bone remodeling. © 2018 American Society for Bone and Mineral Research.

The Role of CTHRC1 in Regulation of Multiple Signaling and Tumor Progression and Metastasis

“…Activated WAIF1 downregulates the expression of Wnt/β-catenin target genes to inhibit the development of endometrial adenocarcinoma [48]. The binding of CTHRC1 to WAIF1 could promote osteoblast differentiation [49]. Therefore, CTHRC1-WAIF1 interaction can be a potential therapeutic target in the future.…”

“…Surprisingly, inhibition of PLC, a membrane-associated enzyme that activates PKC-δ to promote bone formation in noncanonical Wnt signals, did not inhibit CTHRC1-induced alkaline phosphatase (ALP) activity. Therefore, WAIF1 bound by CTHRC1 activates PKC-δ and ERK to stimulate osteoblast differentiation, which is a novel signaling pathway unrelated to the noncanonical Wnt pathway [49]. Therefore, PKC-δ signal may explain the role of CTHRC1 in tumor progressions such as angiogenesis and bone metastasis.…”

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

“…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].…”

“…Importantly, CTHRC1 has emerged as a critical coupling factor that links bone resorption to bone formation by controlling osteoblast-osteoclast cross-talk [10,11,82,83]. The essential regulatory role of CTHRC1 in bone homeostasis has been clearly demonstrated in vivo in mouse studies.…”

Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

“…The culture medium was changed every second day. Osteoclasts were identified by TRAP staining or TRAP activity assay, as described in [35,36].…”