Accelerated Bone Loss in Transgenic Mice Expressing Constitutively Active TGF-β Receptor Type I
Issued Date
2023-06-28
Resource Type
eISSN
14220067
Scopus ID
2-s2.0-85164843392
Pubmed ID
37445982
Journal Title
International journal of molecular sciences
Volume
24
Issue
13
Rights Holder(s)
SCOPUS
Bibliographic Citation
International journal of molecular sciences Vol.24 No.13 (2023)
Suggested Citation
Toejing P., Sakunrangsit N., Pho-on P., Phetkong C., Leelahavanichkul A., Sridurongrit S., Greenblatt M.B., Lotinun S. Accelerated Bone Loss in Transgenic Mice Expressing Constitutively Active TGF-β Receptor Type I. International journal of molecular sciences Vol.24 No.13 (2023). doi:10.3390/ijms241310797 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/88035
Title
Accelerated Bone Loss in Transgenic Mice Expressing Constitutively Active TGF-β Receptor Type I
Other Contributor(s)
Abstract
Transforming growth factor beta (TGF-β) is a key factor mediating the intercellular crosstalk between the hematopoietic stem cells and their microenvironment. Here, we investigated the skeletal phenotype of transgenic mice expressing constitutively active TGF-β receptor type I under the control of Mx1-Cre (Mx1;TβRICA mice). μCT analysis showed decreased cortical thickness, and cancellous bone volume in both femurs and mandibles. Histomorphometric analysis confirmed a decrease in cancellous bone volume due to increased osteoclast number and decreased osteoblast number. Primary osteoblasts showed decreased ALP and mineralization. Constitutive TβRI activation increased osteoclast differentiation. qPCR analysis showed that Tnfsf11/Tnfrsf11b ratio, Ctsk, Sufu, and Csf1 were increased whereas Runx2, Ptch1, and Ptch2 were decreased in Mx1;TβRICA femurs. Interestingly, Gli1, Wnt3a, Sp7, Alpl, Ptch1, Ptch2, and Shh mRNA expression were reduced whereas Tnfsf11/Tnfrsf11b ratio was increased in Mx1;TβRICA mandibles. Similarly, osteoclast-related genes were increased in Mx1;TβRICA osteoclasts whereas osteoblast-related genes were reduced in Mx1;TβRICA osteoblasts. Western blot analysis indicated that SMAD2 and SMAD3 phosphorylation was increased in Mx1;TβRICA osteoblasts, and SMAD3 phosphorylation was increased in Mx1;TβRICA osteoclasts. CTSK was increased while RUNX2 and PTCH1 was decreased in Mx1;TβRICA mice. Microindentation analysis indicated decreased hardness in Mx1;TβRICA mice. Our study indicated that Mx1;TβRICA mice were osteopenic by increasing osteoclast number and decreasing osteoblast number, possibly by suppressing Hedgehog signaling pathways.