biostudies-literatureDelgado-Calle JBLRD VANHLBI NIH HHSNational Institutes of HealthNIAMS NIH HHSU.S. Department of Veterans Affairs2878-2890https://www.ebi.ac.uk/biostudies/studies/S-EPMC5901377biostudies-literatureUnknown32(5)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 bonFASEB journal : official publication of the Federation of American Societies for Experimental BiologyMMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production.PMC5901377R01 AR059357I01 BX0021041 101 BX002104‐01T35 HL110854R01‐AR060332R01‐AR059357R01 AR060332Sanudo CHancock BRiancho JATonra JRDelgado-Calle JMcAndrews KBellido TBruzzaniti ALikine EFSato AYfalseMMP14 is a novel target of PTH signaling in osteocytes that controls resorption by regulating soluble RANKL production.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 bon2018-01-01T00:00:00Z2018 May2025-05-29T22:17:38.326Z2025-05-29T22:17:38.326ZS-EPMC59013772940159310.1096/fj.201700919RRR10.1096/fj.201700919rrr