Osteocyte-Derived CaMKK2 Regulates Osteoclasts and Bone Mass in a Sex-Dependent Manner through Secreted Calpastatin

Autor:	Justin N Williams, Mavis Irwin, Yong Li, Anuradha Valiyakambrath, Brett T Mattingly, Sheel Patel, Mizuho Kittaka, Rebecca N Collins, Nicholas Clough, Emma H Doud, Amber L Mosley, Teresita M Bellido, Angela Bruzzaniti, Lilian I. Plotkin, Jonathan C. Trinidad, William R Thompson, Lynda F. Bonewald, Uma Sankar
Rok vydání:	2023
Předmět:	Organic Chemistry extracellular calpastatin General Medicine Catalysis Computer Science Applications Inorganic Chemistry cell_developmental_biology Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 osteoclasts Physical and Theoretical Chemistry Molecular Biology bone remodeling Spectroscopy osteocytes
Zdroj:	International Journal of Molecular Sciences Volume 24 Issue 5 Pages: 4718
ISSN:	1422-0067
DOI:	10.3390/ijms24054718
Popis:	Calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) regulates bone remodeling through its effects on osteoblasts and osteoclasts. However, its role in osteocytes, the most abundant bone cell type, and the master regulator of bone remodeling, remains unknown. Here we report that the conditional deletion of CaMKK2 from osteocytes using Dentine matrix protein 1 (Dmp1)-8kb-Cre mice led to enhanced bone mass only in female mice owing to a suppression of osteoclasts. Conditioned media isolated from female CaMKK2-deficient osteocytes inhibited osteoclast formation and function in in vitro assays, indicating a role for osteocyte-secreted factors. Proteomics analysis revealed significantly higher levels of extracellular calpastatin, a specific inhibitor of calcium-dependent cysteine proteases calpains, in female CaMKK2 null osteocyte conditioned media, compared to media from female control osteocytes. Further, exogenously added non-cell permeable recombinant calpastatin domain I elicited a marked, dose-dependent inhibition of female wild-type osteoclasts and depletion of calpastatin from female CaMKK2-deficient osteocyte conditioned media reversed the inhibition of matrix resorption by osteoclasts. Our findings reveal a novel role for extracellular calpastatin in regulating female osteoclast function and unravel a novel CaMKK2-mediated paracrine mechanism of osteoclast regulation by female osteocytes.
Databáze:	OpenAIRE
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