Accelerated Bone Loss in Transgenic Mice Expressing Constitutively Active TGF-β Receptor Type I.

TitleAccelerated Bone Loss in Transgenic Mice Expressing Constitutively Active TGF-β Receptor Type I.
Publication TypeJournal Article
Year of Publication2023
AuthorsToejing P, Sakunrangsit N, Pho-On P, Phetkong C, Leelahavanichkul A, Sridurongrit S, Greenblatt MB, Lotinun S
JournalInt J Mol Sci
Date Published2023 Jun 28
KeywordsAnimals, Bone Diseases, Metabolic, Cell Differentiation, Core Binding Factor Alpha 1 Subunit, Hedgehog Proteins, Mice, Mice, Transgenic, Osteoblasts, Osteoclasts, Receptors, Transforming Growth Factor beta

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.

Alternate JournalInt J Mol Sci
PubMed ID37445982
PubMed Central IDPMC10341885
Grant ListDRF66004 andCU_FRB65_hea (5)_011_32_06 / / Faculty Research Grant (DRF66004), Faculty of Dentistry, Thailand Science research and Innova-tion Fund (CU_FRB65_hea (5)_011_32_06), and the Second Century Fund (C2F), Chulalongkorn University. /
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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