Anabolic effect of parathyroid hormone (1-34) to prevent ovariectomy induced bone loss is attenuated in Col1A1-cre floxed monocyte chemotactic protein 1 (MCP1, CCL2) mice.

The anabolic effect of Parathyroid Hormone (PTH 1-34) is a potent anti-osteoporosis treatment. In rat bone, the chemokine MCP1 (also known as CCL2) is induced about 250-fold occurring within 1 h of PTH injection and is the highest induced gene. In mice, we showed previously that global knockout (KO) of MCP1 blocked the anabolic effect of PTH. In the present work, we used cre-lox genetic models to generate cell lineage specific MCP1 KO in the osteoblast/osteocyte lineage by using the type 1 collagen promoter (Col1A1) to drive cre recombinase in mice carrying loxP sites flanking the MCP1 gene (MCP1f/f). In contrast to a 2.6 standard deviation (SD) increase in total bone in the proximal tibial metaphysis (p = 4 × 10-9) in control mice, there was no response to anabolic PTH in mice in which the MCP1 gene was deleted (MCP1f/f Col-cre+, p = 0.6). We then tested whether ovariectomy (OVX) induced bone loss could be suppressed by simultaneous anabolic PTH treatment (OVX-PTH) in such animals. In control animals, OVX resulted in a 2.0 SD decrease in bone density. OVX-PTH treated animals had bone density 1.6 SD higher than baseline untreated and 3.6 SD increased from the low OVX level. In contrast, the anabolic PTH effect was significantly blunted (p = 0.01) in OVX MCP1f/f Col-cre + animals with a 1.4 SD change. These data suggest a role for osteoblast/osteocyte expressed MCP1 in the anabolic effect of PTH.