期刊
FASEB JOURNAL
卷 32, 期 5, 页码 2878-2890出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201700919RRR
关键词
osteoclasts; osteoblasts; antiresorptive; osteoporosis
资金
- U.S. Department of Veterans Affairs [1 I01 BX002104-01]
- U.S. National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01-AR059357, R01-AR060332]
- NIH National Heart, Lung, and Blood Institute [T35 HL1 10854-01]
- American Society of Hematology
- Instituto de Salud Carlos III [PI12/615]
- European Union through Fonds Europeen de Developpement Economique et Regional (FEDER) funds
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 (caPTH1R(Ot)) and in bones from mice exposed to elevated PTH levels but not in mice lacking [conditional knockout (cKO)] the PTH1R in Ots (cKOPTH1R(Ot)). Furthermore, PTH upregulates MMP14 in human bone cultures and in Ot-enriched bones from floxed control mice but not from cKOPTH1R(Ot) mice. MMP14 activity increases soluble receptor activator of NF-kappa B ligand production, which in turn, stimulates osteoclast differentiation and resorption. Pharmacologic inhibition of MMP14 activity reduced the high bone remodeling exhibited by caPTH1R(Ot) 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.
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