Extracellular acidification augments sclerostin and osteoprotegerin production by Ocy454 mouse osteocytes

Kaori Ikezaki-Amada; Yoichi Miyamoto; Kiyohito Sasa; Atsushi Yamada; Mitsuhiro Kinoshita; Kentaro Yoshimura; Ryota Kawai; Fumiko Yano; Tatsuo Shirota; Ryutaro Kamijo

doi:10.1016/j.bbrc.2022.01.111

Extracellular acidification augments sclerostin and osteoprotegerin production by Ocy454 mouse osteocytes

Biochem Biophys Res Commun. 2022 Mar 15:597:44-51. doi: 10.1016/j.bbrc.2022.01.111. Epub 2022 Jan 31.

Affiliations

¹ Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan; Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.
² Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan. Electronic address: yoichim@dent.showa-u.ac.jp.
³ Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan.
⁴ Department of Biochemistry, Showa University School of Dentistry, Tokyo, Japan; Department of Orthodontics, Showa University School of Dentistry, Tokyo, Japan.
⁵ Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, Tokyo, Japan.

PMID: 35123265
DOI: 10.1016/j.bbrc.2022.01.111

Abstract

Osteocytes sense the microenvironmental stimuli, including mechanical stress, and regulate bone resorption by osteoclasts and bone formation by osteoblasts. Diabetes and cancer metastasis to bone raise l-lactic acid in the bone tissue, causing acidification. Here, we investigated the effects of l-lactic acid and extracellular acidification on the function of mouse Ocy454 osteocytes. L- and d-lactic acid with low chiral selectivity and acidification of the medium raised the production of sclerostin and osteoprotegerin by Ocy454 cells. The mRNA expression of their genes increased after either treatment of L- and d-lactic acid or acidification of the medium. Furthermore, the conditioned medium of Ocy454 cells cultured in an acidic environment suppressed the induction of alkaline phosphatase activity in MC3T3-E1 cells, which was recovered by the anti-sclerostin antibody. While it is reported that HDAC5 inhibits the transcription of the sclerostin gene, extracellular acidification reduced the nuclear localization of HDAC5 in Ocy454 cells. While calmodulin kinase II (CaMKII) is known to phosphorylate and induce extranuclear translocation of HDAC5, KN-62, an inhibitor of CaMKII lowered the expression of the sclerostin gene in Ocy454 cells. Collectively, extracellular acidification is a microenvironmental factor that modulates osteocyte functions.

Keywords: Acidification; Osteocytes; Osteoprotegerin; Sclerostin.