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Commun Biol. 2019 Mar 1;2:86. doi: 10.1038/s42003-019-0334-5. eCollection 2019.

Murine osteoclasts secrete serine protease HtrA1 capable of degrading osteoprotegerin in the bone microenvironment.

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1Research Center for Genomic Medicine, Saitama Medical University, Saitama, 350-1298 Japan.
2Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, 331-9530 Japan.
3Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, 331-9530 Japan.
4Institutes for Oral Science, Matsumoto Dental University, Nagano, 399-0781 Japan.
5Department of Biochemistry, Matsumoto Dental University, Nagano, 399-0781 Japan.
6Center for Genomic and Regenerative Medicine, Juntendo University, Tokyo, 113-8421 Japan.


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.

Conflict of interest statement

The authors declare no competing interests.

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