A SMOC2 variant inhibits BMP signaling by competitively binding to BMPR1B and causes growth plate defects

Heterozygous transcriptional signatures unmask variable premature termination codon (PTC) burden alongside pathway-specific adaptations in blood outgrowth endothelial cells from patients with nonsense DNA variants causing hereditary hemorrhagic telangiectasia

“…This highlights lower alignments in HHT BOECs to SMAD3 and FOS that encode proteins transmitting or regulate TGF-β signalling; to BMP6 and HES1 (induced by BMP9 55 ); and to genes encoding extracellular matrix proteins now recognised to have roles in BMP crosslinking (POSTN, LOXL2), BMP antagonism (SMOC2), and BMP ligand presentation (FBN1). [56][57][58][59][60][61][62][63][64][65] We concluded that the data were in-keeping with expectations 24 for consequences of perturbed BMP/TGF-β signalling resulting from heterozygous loss of ENG, ACVRL1 or SMAD4 function.…”

“…57, 58 Furthermore, experimental studies link ENG , ACVRL1 and SMAD4 deficiency to reductions in endothelial integrity, 21, 23, 24 relevant to the core clinical HHT phenotype of hemorrhage. 5–9 Amongst the top 50 HHT-differentially aligned genes, many encode extracellular proteins that regulate TGF-β/BMP signalling including periostin 56 ( POSTN) , fibulin-6/hemicentin 1 59, 60 ( HMCN1) , lysyl oxidase-like 2 61 ( LOXL2 ), SPARC-related modular calcium binding protein 2 62 ( SMOC2) , laminin receptor 1 ( RSPA ), 63 and fibrillin 1 ( FBN1 , Figure 4F, Supplementary Figure 7) 58 Likely relevance was further enhanced because BMP/TGF-β ligand release from extracellular pools is by matrix metallopeptidases, 64, 65 a further GO term enriched in the HHT BOEC datasets (through 8 genes, most significantly ADAMTS18 , and MMP24 , Figure 4F, Supplementary Figure 7). Our initial expectation was that their modulation may be further cellular adaptive responses that enable more ACVRL1 +/- , ENG +/- and SMAD4 +/- BOECs to survive, analogous to lower ALK5 and ALK1 receptor expression/signalling.…”

Application of BMP in Bone Tissue Engineering

“…BMP stimulates the first stage of endochondral ossification, including effective stem cell recruitment and cartilage formation. BMP plays an important role in endochondral bone development and has various functions in bone formation, including bone morphogenesis, growth plate development and osteoblast differentiation ( Wu et al, 2016 ; Long et al, 2021 ; Strong et al, 2021 ; Yang et al, 2021 ). Bone remodelling is a physiological process involving absorption of old bone and formation of new bone.…”

“…During osteoblastic differentiation, BMSCs are controlled by Runx2 and Osx genes, which are considered to be key genes for osteoblastic differentiation. Among them, Runx2 plays a leading role in the entire differentiation process, while the BMP signalling pathway directly affects the expression of Runx2, therefore, BMPs can more effectively induce osteoblast differentiation and regulate bone formation ( Yokouchi et al, 1996 ; Lieberman et al, 1998 ; Baltzer et al, 2000 ; Krishnan et al, 2001 ; Sojo et al, 2005 ; Bessa et al, 2008 ; Seo et al, 2014 ; Teotia et al, 2017 ; Pini et al, 2018 ; Ball et al, 2019 ; Chen et al, 2019 ; Long et al, 2021 ).…”

Instructive cartilage regeneration modalities with advanced therapeutic implantations under abnormal conditions

“…Similarly, platelet-derived growth factor (PDGF) also participates in the migration of MSCs [ 104 ]. In the later stage of growth plate regeneration, VEGF and BMP are responsible for tissue remodeling by reconstructing the blood supply and inducing osteogenic differentiation of infiltrated MSCs [ [105] , [106] , [107] , [108] ]. To restore the natural function of growth plates, it is necessary to construct a biomimetic biochemical microenvironment during growth plate regeneration by incorporating growth factors into scaffolds and controlling their releasing order.…”