MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production.

Abstract

Parathyroid hormone (PTH) affects the skeleton by acting on osteocytes (Ots) in bone through yet unclear mechanisms. We report that matrix metalloproteinase 14 (MMP14) expression/activity are increased in bones from mice with genetic constitutive activation (ca) of the PTH receptor 1 (PTH1R) in Ots (caPTH1ROt) and in bones from mice exposed to elevated PTH levels but not in mice lacking [conditional knockout (cKO)] the PTH1R in Ots (cKOPTH1ROt). Furthermore, PTH upregulates MMP14 in human bone cultures and in Ot-enriched bones from floxed control mice but not from cKOPTH1ROt mice. MMP14 activity increases soluble receptor activator of NF-κΒ ligand production, which in turn, stimulates osteoclast differentiation and resorption. Pharmacologic inhibition of MMP14 activity reduced the high bone remodeling exhibited by caPTH1ROt mice or induced by chronic PTH elevation and decreased bone resorption but allowed full stimulation of bone formation induced by PTH injections, thereby potentiating bone gain. Thus, MMP14 is a new member of the intricate gene network activated in Ots by PTH1R signaling that can be targeted to adjust the skeletal responses to PTH in favor of bone preservation.-Delgado-Calle, J., Hancock, B., Likine, E. F., Sato, A. Y., McAndrews, K., Sanudo, C., Bruzzaniti, A., Riancho, J. A., Tonra, J. R., Bellido, T. MMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production.

• Authors: Jesus Delgado-Calle, Benjamin Hancock, Elive F Likine, Amy Y Sato, Kevin McAndrews, Carolina Sanudo, Angela Bruzzaniti, Jose A Riancho, James R Tonra, Teresita Bellido
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 32 Issue 5 Pg. 2878-2890 (05 2018) ISSN: 1530-6860 [Electronic] United States
• PMID: 29401593 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Mmp14 protein, mouse
• PTH1R protein, human
• PTH1R protein, mouse
• Parathyroid Hormone
• RANK Ligand
• Receptor, Parathyroid Hormone, Type 1
• TNFSF11 protein, human
• Tnfsf11 protein, mouse
• MMP14 protein, human
• Matrix Metalloproteinase 14

Topics

• Animals
• Bone Resorption (genetics, metabolism)
• Cells, Cultured
• Gene Regulatory Networks (physiology)
• Matrix Metalloproteinase 14 (genetics, metabolism)
• Mice
• Mice, Knockout
• Osteoclasts (cytology, metabolism)
• Osteocytes (cytology, metabolism)
• Osteogenesis (physiology)
• Parathyroid Hormone (genetics, metabolism)
• RANK Ligand (biosynthesis, genetics)
• Receptor, Parathyroid Hormone, Type 1 (genetics, metabolism)
• Signal Transduction (physiology)