Intermittent PTH administration converts quiescent lining cells to active osteoblasts


Sang Wan Kim, Paola Divieti Pajevic, Martin Selig, Kevin J. Barry, Jae-Yeon Yang, Chan Soo Shin, Wook-Young Baek, Jung-Eun Kim, Henry M. Kronenberg


Intermittent administration of parathyroid hormone (PTH) increases bone mass, at least in part, by increasing osteoblast number. One possible source of osteoblasts might be conversion of inactive lining cells to osteoblasts, and indirect evidence is consistent with this hypothesis. To better understand the possible effect of PTH on lining cell activation, a lineage tracing study was conducted using an inducible gene system. Dmp1-CreERt2 mice were crossed with ROSA26R reporter mice to render targeted mature osteoblasts and their descendents, lining cells and osteocytes, detectable by X-gal staining. Dmp1-CreERt2(+):ROSA26R mice were injected with 0.25 mg 4-OH-tamoxifen (4-OHTam) on postnatal day 3, 5, 7, 14, and 21. The animals were sacrificed on postnatal day 23, 33 or 43 (2, 12 or 22 days after the last 4-OHTam injection). On day 43, mice were challenged with a subcutaneous injection of human PTH (1–34, 80 µg/kg) or vehicle once daily for 3 days. By 22 days after the last 4-OHTam injection, most X-gal (+) cells on the periosteal surfaces of both the calvaria and tibia were flat. Moreover, bone formation rate and collagen I(α1) mRNA expression were decreased at day 43 compared to day 23. After 3 days of PTH injections, the thickness of X-gal (+) cells increased, as did their expression of osteocalcin and collagen I(α1) mRNA. Electron microscopy revealed X-gal-associated chromagen particles in both thin cells prior to PTH administration and cuboidal cells following PTH administration. These data support the hypothesis that intermittent PTH treatment can increase osteoblast number by converting lining cells to mature osteoblasts in vivo.

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