Forced expression of mouse progerin attenuates the osteoblast differentiation interrupting [beta]-catenin signal pathway in vitro

• Published in: Cell and tissue research Vol. 375; no. 3; p. 655
• Main Authors: Tsukune, Naoya, Naito, Masako, Ohashi, Akiko, Ninomiya, Tadashi, Sato, Shuichi, Takahashi, Tomihisa
• Format: Journal Article
• Language: English
• Published: Springer 01-03-2019
• Subjects: Amino acids; Cell differentiation; Collagen; Messenger RNA; Phosphatases; Progeria; RNA
• ISSN: 0302-766X
• DOI: 10.1007/s00441-018-2930-y

Nuclear protein, lamin A, which is a component of inner membrane on nucleoplasm, plays a role in nuclear formation and cell differentiation. The expression of mutated lamin A, termed progerin, causes a rare genetic aging disorder, Hutchinson-Gilford progeria syndrome, which shows abnormal bone formation with the decrease in a number of osteoblasts and osteocytes. However, exact molecular mechanism how progerin exerts depressive effects on osteogenesis has not been fully understood. Here, we created mouse lamin A dC50 cDNA encoding progerin that lacks 50 amino acid residues at C-terminus, transfected it in mouse preosteoblast-like MC3T3-E1 cells, and examined the changes in osteoblast phenotype. When lamin A dC50-expressed cells were cultured with differentiation-inductive medium, alkaline phosphatase (ALP) activity and mRNA levels of major osteoblast markers, type I collagen (Col1), bone sialoprotein (BSP), dentine matrix protein 1 (DMP1), and Runx2 were significantly decreased, and no mineralized nodules were detected as seen in control cells expressing empty vector. In the culture with mineralization-inductive medium, mRNA levels of BSP, osteocalcin, DMP1, Runx2, and osterix were strongly decreased parallel with loss of mineralization in lamin A dC50-expressed cells, while mineralized nodules appear at 21 days in control cells. Furthermore, lamin A dC50 expression was depressed nuclear localization of [beta]-catenin with the decrease of GSK-3[beta] phosphorylation level. These results suggest that lamin A dC50 depresses osteoblast differentiation in both early and late stages, and it negatively regulates [beta]-catenin activity interacting with GSK-3[beta] in cytoplasm.