A Novel Role for the BMP Antagonist Noggin in Sensitizing Cells to Non-canonical Wnt-5a/Ror2/Disheveled Pathway Activation

Abstract

Mammalian limb development is driven by the integrative input from several signaling pathways; a failure to receive or a misinterpretation of these signals results in skeletal defects. The brachydactylies, a group of overlapping inherited human hand malformation syndromes, are mainly caused by mutations in BMP signaling pathway components. Two closely related forms, Brachydactyly type B2 (BDB2) and BDB1 are caused by mutations in the BMP antagonist Noggin (NOG) and the atypical receptor tyrosine kinase ROR2 that acts as a receptor in the non-canonical Wnt pathway. Genetic analysis of Nog and Ror2 functional interaction via crossing Noggin and Ror2 mutant mice revealed a widening of skeletal elements in compound but not in any of the single mutants, thus indicating genetic interaction. Since ROR2 is a non-canonical Wnt co-receptor specific for Wnt-5a we speculated that this phenotype might be a result of deregulated Wnt-5a signaling activation, which is known to be essential for limb skeletal elements growth and patterning. We show that Noggin potentiates activation of the Wnt-5a-Ror2-Disheveled (Dvl) pathway in mouse embryonic fibroblast (MEF) cells in a Ror2-dependent fashion. Rat chondrosarcoma chondrocytes (RCS), however, are not able to respond to Noggin in this fashion unless growth arrest is induced by FGF2. In summary, our data demonstrate genetic interaction between Noggin and Ror2 and show that Noggin can sensitize cells to Wnt-5a/Ror2-mediated non-canonical Wnt signaling, a feature that in cartilage may depend on the presence of active FGF signaling. These findings indicate an unappreciated function of Noggin that will help to understand BMP and Wnt/PCP signaling pathway interactions.

Biscarbamate Cross-Linked Low-Molecular-Weight Polyethylenimine for Delivering Anti-chordin siRNA into Human Mesenchymal Stem Cells for Improving Bone Regeneration

“… Kwong et al (2008) and Schneider et al (2014) reported that Chordin knockdown enhanced the osteogenic of bone marrow and adipose tissue-derived stem cells in vitro . Noggin was also a BMP-2 antagonist which was widely studied ( Albers et al, 2012 ; Bernatik et al, 2017 ). The effect of Noggin on the osteogenic differentiation of BMSCs was bilateral.…”

Anticancer effects of oridonin on colon cancer are mediated via BMP7/p38 MAPK/p53 signaling

“…BMPs belong to TGF-β superfamily, and play a crucial role in bone development, fracture repair, and in the pathogenesis of certain solid tumors by regulating cell differentiation, proliferation and apoptosis (9)(10)(11). Currently, ~20 BMPs have been identified in human cells.…”

“…Bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor (TGF)-β superfamily are associated with multiple physiological functions, including the regulation of cell differentiation, proliferation and apoptosis (9)(10)(11). BMP2, BMP4 and BMP7 can inhibit the proliferation of colon cancer cells (9,12).…”

Treatments and Preventative Measures for Trauma‐Induced Heterotopic Ossification: A Review

“…Although small animal models cannot directly mimic the formation of clinically relevant HO, each type of animal study provides the opportunity to better understand the pathophysiology and pathogenesis under unique circumstances. A comprehensive evaluation of the mechanistic pathways of bone growth, healing, and complications that may contribute to HO is beyond the scope of this review but some of the discussions are provided for further investigation 28, 29, 30, 31, 32, 33, 34, 35, 36, 37. With improved understanding, better physical and pharmacological therapeutic protocols can be developed for use in human patients.…”

“…Several animal models have been developed to facilitate a better understanding of the pathogenesis and outcomes of various types of trauma and the occurrence of HO. 25,26 They are used to elucidate several aspects of HO formation, including severity at specific locations, mechanism of injury, and timing of HO formation after injury and have been of great importance to furthering HO research efforts (see Table 1 11,[26][27][28][29][30][31][32][33][34][35][36] ). Outside of specific models aimed directly at studying war-time injuries, such as the Walter-Reed polytrauma and amputation models, few animal models focus directly on the contribution of blunt-force trauma to the formation of HO.…”