VWC2 Increases Bone Formation Through Inhibiting Activin Signaling

Abstract

By a bioinformatics approach, we have identified a novel cysteine knot protein member, VWC2 (von Willebrand factor C domain containing 2) previously known as Brorin. Since Brorin has been proposed to function as a bone morphogenetic protein (BMP) antagonist, we investigated the binding of Brorin/VWC2 to several BMPs; however, none of the BMPs tested were bound to VWC2. Instead, the βA subunit of activin was found as a binding partner among transforming growth factor (TGF)-β superfamily members. Here, we show that Vwc2 gene expression is temporally upregulated early in osteoblast differentiation, VWC2 protein is present in bone matrix, and localized at osteoblasts/osteocytes. Activin A-induced Smad2 phosphorylation was inhibited in the presence of exogenous VWC2 in MC3T3-E1 osteoblast cell line and primary osteoblasts. The effect of VWC2 on ex vivo cranial bone organ cultures treated with activin A was investigated, and bone morphometric parameters decreased by activin A were restored with VWC2. When we further investigated the biological mechanism how VWC2 inhibited the effects of activin A on bone formation, we found that the effects of activin A on osteoblast cell growth, differentiation, and mineralization were reversed by VWC2. Taken together, a novel secretory protein, VWC2 promotes bone formation by inhibiting Activin-Smad2 signaling pathway.

Genomic inbreeding trends, influential sire lines and selection in the global Thoroughbred horse population

“…For example, the deleted in lymphocytic leukemia 7 gene (DLEU7) is associated with growth traits in chickens 51 and overgrowth in humans 52 and may therefore contribute to stature in Thoroughbreds. In bone physiology, the von Willebrand factor C domain containing 2 gene (VWC2), a bone morphogenic protein, promotes bone formation, regeneration and healing 53,54 . In the context of Thoroughbred musculature, the multiple EGF like domains 10 gene (MEGF10) controls muscle cell proliferation and is involved in the regulation of myogenesis 55,56 and the collagen type VI alpha 3 chain gene (COL6A3) plays a major role in the maintenance of strength of muscle and connective tissue 57 .…”

Transcriptome analysis of the testes of male chickens with high and low sperm motility

“…REC8 inhibited MSTRG.15920.1 and MSTRG.11860.2, whereas VWC2 inhibited MSTRG.11860.2. REC8 affects sperm meiosis, and VWC2 is a bone morphogenetic protein antagonist ( Almehmadi et al, 2018 ). BMP4 promotes the formation of primordial germ cells in chickens ( Zuo et al, 2019 ).…”

“…REC8 is expressed in mouse spermatocytes and oocytes ( Lee et al, 2002 2003b ; Rong et al, 2016 ) and has a key role in spermatogenesis and oogenesis ( Xu et al, 2005 ; Lin et al, 2020 ). The cysteine junction protein VWC2 increases bone formation through an antagonistic effect on BMP signaling ( Almehmadi et al, 2018 ). The lncRNA MSTRG.22136.1 regulated the alpha-B crystallin gene CRYAB.…”

Genomic inbreeding trends in the global Thoroughbred horse population driven by influential sire lines and selection for exercise trait-related genes

“…For example, the deleted in lymphocytic leukemia 7 gene ( DLEU7 ) is associated with growth traits in chickens [31] and overgrowth in humans [32] and may therefore contribute to stature in Thoroughbreds. In bone physiology, the von Willebrand factor C domain containing 2 gene ( VWC2 ), a bone morphogenic protein, promotes bone formation, regeneration and healing [35, 74]. In the context of Thoroughbred musculature, the multiple EGF like domains 10 gene ( MEGF10 ) controls muscle cell proliferation and is involved in the regulation of myogenesis [50, 51] and the collagen type VI alpha 3 chain gene ( COL6A3 ) plays a major role in the maintenance of strength of muscle and connective tissue [45].…”