Serum calcium-decreasing factor, caldecrin, inhibits receptor activator of NF-κB ligand (RANKL)-mediated Ca2+ signaling and actin ring formation in mature osteoclasts via suppression of Src signaling pathway.

Abstract

Osteoclasts are essential for bone dynamics and calcium homeostasis. Recently, we reported that serum calcium-decreasing factor, caldecrin, which is a secretory-type serine protease isolated from the pancreas, inhibits osteoclast differentiation by suppression of NFATc1 activity regardless of its own protease activity (Hasegawa, H., Kido, S., Tomomura, M., Fujimoto, K., Ohi, M., Kiyomura, M., Kanegae, H., Inaba, A., Sakagami, H., and Tomomura, A. (2010) Serum calcium-decreasing factor, caldecrin, inhibits osteoclast differentiation by suppression of NFATc1 activity. J. Biol. Chem. 285, 25448-25457). Here, we investigated the effects of caldecrin on the function of mature osteoclasts by treatment with receptor activator of NF-κB ligand (RANKL). Caldecrin inhibited the RANKL-stimulated bone resorptive activity of mature osteoclasts. Furthermore, caldecrin inhibited RANKL-mediated sealing actin ring formation, which is associated with RANKL-evoked Ca(2+) entry through transient receptor potential vanilloid channel 4. The inhibitors of phospholipase Cγ, Syk, and c-Src suppressed RANKL-evoked Ca(2+) entry and actin ring formation of mature osteoclasts. Interestingly, caldecrin significantly inhibited RANKL-stimulated phosphorylation of c-Src, Syk, phospholipase Cγ1 and Cγ2, SLP-76, and Pyk2 but not that of ERK, JNK, or Akt. Caldecrin inhibited RANKL-stimulated c-Src kinase activity and c-Src·Syk association. These results suggest that caldecrin inhibits RANKL-stimulated calcium signaling activation and cytoskeletal organization by suppression of the c-Src·Syk pathway, which may in turn reduce the bone resorptive activity of mature osteoclasts. Thus, caldecrin is capable of acting as a negative regulator of osteoclastogenesis and osteoclast function of bone resorption.

• Authors: Mineko Tomomura, Hiroya Hasegawa, Naoto Suda, Hiroshi Sakagami, Akito Tomomura
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 22 Pg. 17963-74 (May 25 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22461633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• RANK Ligand
• Tnfsf11 protein, mouse
• src-Family Kinases
• Serine Endopeptidases
• caldecrin

Topics

• Actins (metabolism)
• Animals
• Bone Resorption
• Calcium Signaling (physiology)
• Cell Line
• Humans
• Mice
• Osteoclasts (enzymology, metabolism)
• RANK Ligand (antagonists & inhibitors, physiology)
• Serine Endopeptidases (physiology)
• src-Family Kinases (metabolism)