Murine osteoclasts secrete serine protease HtrA1 capable of degrading osteoprotegerin in the bone microenvironment.
Animals
Bone Marrow Cells
/ metabolism
Bone and Bones
/ metabolism
Cell Differentiation
Cells, Cultured
Cellular Microenvironment
/ genetics
High-Temperature Requirement A Serine Peptidase 1
/ genetics
Macrophages
/ metabolism
Matrix Metalloproteinase 9
/ metabolism
Mice
Osteoblasts
/ metabolism
Osteoclasts
/ metabolism
Osteogenesis
/ genetics
Osteoprotegerin
/ genetics
Proteolysis
Sequence Analysis, RNA
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
2019
2019
Historique:
received:
29
05
2018
accepted:
01
02
2019
entrez:
12
3
2019
pubmed:
12
3
2019
medline:
12
3
2019
Statut:
epublish
Résumé
Osteoclasts are multinucleated cells responsible for bone resorption. The differentiation of osteoclasts from bone marrow macrophages (BMMs) is induced by receptor activator of NF-κB ligand (RANKL). Osteoprotegerin (OPG), a decoy receptor of RANKL, inhibits osteoclastogenesis by blocking RANKL signaling. Here we investigated the degradation of OPG in vitro. Osteoclasts, but not BMMs, secreted OPG-degrading enzymes. Using mass spectrometry and RNA-sequencing analysis, we identified high-temperature requirement A serine peptidase 1 (HtrA1) as an OPG-degrading enzyme. HtrA1 did not degrade OPG pre-reduced by dithiothreitol, suggesting that HtrA1 recognizes the three-dimensional structure of OPG. HtrA1 initially cleaved the amide bond between leucine 90 and glutamine 91 of OPG, then degraded OPG into small fragments. Inhibitory activity of OPG on RANKL-induced osteoclastogenesis was suppressed by adding HtrA1 in RAW 264.7 cell cultures. These results suggest that osteoclasts potentially prepare a microenvironment suitable for osteoclastogenesis. HtrA1 may be a novel drug target for osteoporosis.
Identifiants
pubmed: 30854478
doi: 10.1038/s42003-019-0334-5
pii: 10.1038/s42003-019-0334-5
pmc: PMC6397181
doi:
Substances chimiques
Osteoprotegerin
0
High-Temperature Requirement A Serine Peptidase 1
EC 3.4.21.-
HTRA1 protein, human
EC 3.4.21.-
HtrA1 protein, mouse
EC 3.4.21.-
Matrix Metalloproteinase 9
EC 3.4.24.35
Types de publication
Journal Article
Langues
eng
Pagination
86Déclaration de conflit d'intérêts
The authors declare no competing interests.
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