Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2

Kogawa, Masakazu, Wijenayaka, Asiri R., Ormsby, Renee T., Thomas, Gethin P., Anderson, Paul H., Bonewald, Lynda F., Findlay, David M. and Atkins, Gerald J. (2013) Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. Journal of Bone and Mineral Research, 28 12: 2436-2448. doi:10.1002/jbmr.2003

Author Kogawa, Masakazu
Wijenayaka, Asiri R.
Ormsby, Renee T.
Thomas, Gethin P.
Anderson, Paul H.
Bonewald, Lynda F.
Findlay, David M.
Atkins, Gerald J.
Title Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2
Journal name Journal of Bone and Mineral Research   Check publisher's open access policy
ISSN 0884-0431
Publication date 2013-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1002/jbmr.2003
Open Access Status Not yet assessed
Volume 28
Issue 12
Start page 2436
End page 2448
Total pages 13
Place of publication Malden, MA United States
Publisher Wiley-Blackwell Publishing, Inc.
Language eng
Subject 2732 Orthopedics and Sports Medicine
2712 Endocrinology, Diabetes and Metabolism
Abstract The osteocyte product sclerostin is emerging as an important paracrine regulator of bone mass. It has recently been shown that osteocyte production of receptor activator of NF-κB ligand (RANKL) is important in osteoclastic bone resorption, and we reported that exogenous treatment of osteocytes with sclerostin can increase RANKL-mediated osteoclast activity. There is good evidence that osteocytes can themselves liberate mineral from bone in a process known as osteocytic osteolysis. In the current study, we investigated sclerostin-stimulated mineral dissolution by human primary osteocyte-like cells (hOCy) and mouse MLO-Y4 cells. We found that sclerostin upregulated osteocyte expression of carbonic anhydrase 2 (CA2/Car2), cathepsin K (CTSK/Ctsk), and tartrate-resistant acid phosphatase (ACP5/Acp5). Because acidification of the extracellular matrix is a critical step in the release of mineral from bone, we further examined the regulation by sclerostin of CA2. Sclerostin stimulated CA2 mRNA and protein expression in hOCy and in MLO-Y4 cells. Sclerostin induced a decrease in intracellular pH (pHi) in both cell types as well as a decrease in extracellular pH (pHo) and the release of calcium ions from mineralized substrate. These effects were reversed in the co-presence of the carbonic anhydrase inhibitor, acetozolamide. Car2-siRNA knockdown in MLO-Y4 cells significantly inhibited the ability of sclerostin to both reduce the pHo and release calcium from a mineralized substrate. Knockdown in MLO-Y4 cells of each of the putative sclerostin receptors, Lrp4, Lrp5 and Lrp6, using siRNA, inhibited the sclerostin induction of Car2, Catk and Acp5 mRNA, as well as pHo and calcium release. Consistent with this activity of sclerostin resulting in osteocytic osteolysis, human trabecular bone samples treated ex vivo with recombinant human sclerostin for 7 days exhibited an increased osteocyte lacunar area, an effect that was reversed by the co-addition of acetozolamide. These findings suggest a new role for sclerostin in the regulation of perilacunar mineral by osteocytes.
Keyword Carbonic anhydrase 2
Osteocytic osteolysis
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 565372
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
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