Abstract
The bone morphogenetic protein (BMP) and Wnt signaling pathways both contribute essential roles in regulating bone mass. However, the molecular interactions between these pathways in osteoblasts are poorly understood. We recently reported that osteoblast-targeted conditional knockout (cKO) of BMP receptor type IA (BMPRIA) resulted in increased bone mass during embryonic development, where diminished expression of Sost as a downstream effector of BMPRIA resulted in increased Wnt/β-catenin signaling. Here, we report that Bmpr1a cKO mice exhibit increased bone mass during weanling stages, again with evidence of enhanced Wnt/β-catenin signaling as assessed by Wnt reporter TOPGAL mice and TOPFLASH luciferase. Consistent with negative regulation of the Wnt pathway by BMPRIA signaling, treatment of osteoblasts with dorsomorphin, an inhibitor of Smad-dependent BMP signaling, enhanced Wnt signaling. In addition to Sost, Wnt inhibitor Dkk1 also was downregulated in cKO bone. Expression levels of Dkk1and Sost were upregulated by BMP2 treatment and downregulated by Noggin. Moreover, expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype. These effectors are differentially regulated by mitogen-activated protein kinase (MAPK) p38 because pretreatment of osteoblasts with SB202190 blocked BMP2-induced Dkk1 expression but not Sost. These results demonstrate that BMPRIA in osteoblasts negatively regulates endogenous bone mass and Wnt/β-catenin signaling and that this regulation may be mediated by the activities of Sost and Dkk1. This study highlights several interactions between BMP and Wnt signaling cascades in osteoblasts that may be amenable to therapeutic intervention for the modification of bone mass density. © 2010 American Society for Bone and Mineral Research
Highlights
Bone morphogenetic proteins (BMPs), originally discovered as inducers of ectopic bone,(3) are members of the transforming growth factor b (TGF-b) superfamily.[1,2] bone morphogenetic protein (BMP) signals, like those of other TGF-b family members, are mediated by the concerted activation of type I and type II serine-threonine kinase receptors.[4]
We recently reported that loss of BMP receptor type IA (BMPRIA) in osteoblasts during embryogenesis upregulates canonical Wnt signaling in mice.[14]. To assay canonical Wnt signaling in situ, conditional knockout (cKO) mice were mated with TOPGAL Wnt reporter mice, which express a b-galactosidase transgene driven by a T-cell factor (TCF) b-catenin-responsive promoter.[29] cKO TOPGAL mice demonstrated increased Wnt signaling activity in cKO rib bones at P14 compared with controls when assessed by whole mount (Fig. 2A, upper panels) and sections via b-gal staining, as were calvariae at P10 and P14
We previously reported that loss of BMPRIA-mediated signaling resulted in increased bone mass in embryos and adults[14,15] and discovered that sclerostin/Sost is a downstream target of BMPRIA signaling during embryogenesis that inhibits Wnt to regulate
Summary
Bone morphogenetic proteins (BMPs), originally discovered as inducers of ectopic bone,(3) are members of the transforming growth factor b (TGF-b) superfamily.[1,2] BMP signals, like those of other TGF-b family members, are mediated by the concerted activation of type I and type II serine-threonine kinase receptors.[4]. The osteogenic function of BMPs has been documented extensively, with numerous in vitro studies supporting a critical role of BMP signaling in osteoblastogenesis.[8] While constitutive activation of BMP signaling in muscle appears to induce ectopic ossification in patients with fibrodysplasia ossificans progressiva[9] and in a mouse model,(10) the physiologic effects of BMP signaling on endogenous bone formation in vivo have not been fully elucidated. BMP2 has been reported to induce both Wnt3a and Wnt/b-catenin signaling,(21–23) whereas Wnt3a, in turn, enhances BMP4 expression.[24] Wnt3a has been reported to repress BMP2-dependent Id1 expression.[25] In contrast, we recently demonstrated that loss of BMPRIA signaling in osteoblasts downregulates sclerostin/Sost and upregulates Wnt/b-catenin signaling, resulting in increased bone mass during embryonic stages.[14] Our results provide a potential mechanism by which BMP signaling in osteoblasts negatively regulates Wnt signaling to control fetal bone mass. In addition to Sost, we find that Wnt inhibitor Dkk is a downstream target of BMPRIA signaling in osteoblasts, lending further support for a negative regulation of Wnt signaling via BMPRIA
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
