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Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone
Author(s) -
Locklin Rachel M.,
Khosla Sundeep,
Turner Russell T.,
Riggs B. Lawrence
Publication year - 2003
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10490
Subject(s) - endocrinology , medicine , rankl , parathyroid hormone , osteoblast , chemistry , bone resorption , bone remodeling , osteoprotegerin , alkaline phosphatase , osteopontin , runx2 , anabolism , receptor , activator (genetics) , calcium , biochemistry , enzyme , in vitro
Parathyroid hormone (PTH) has biphasic effects on bone: continuous treatment is catabolic whereas intermittent treatment is anabolic. The mechanism(s) responsible for these differing effects are still unclear, partly because of the previous non‐availability of a model system in which effects on both formation and resorption indices could be studied concomitantly. In cultured marrow cells from 6‐week old C57BL/6 mice, we demonstrated that 4 days of intermittent PTH treatment increased mRNA for osteoblast differentiation markers (Runx2, alkaline phosphatase (AP), and type I procollagen (COL1A1) whereas continuous treatment resulted in production of large numbers of TRAP‐positive multinucleated osteoclasts. Although IGF‐I mRNA did not increase after intermittent treatment, it was consistently higher than after continuous treatment, and the addition of an anti‐IGF‐I neutralizing antibody prevented the increase in bone formation indices observed with intermittent treatment. By contrast, after continuous treatment, gene expression of RANK ligand (RANKL) was increased and that of osteoprotegerin (OPG) was decreased, resulting in a 25‐fold increase in the RANKL/OPG ratio. In this model system, the data suggest that intermittent PTH treatment enhances osteoblast differentiation through an IGF‐I dependent mechanism and continuous PTH treatment enhances osteoclastogenesis through reciprocal increases in RANKL and decreases in OPG. J. Cell. Biochem. 89: 180–190, 2003. © 2003 Wiley‐Liss, Inc.