Molecular and cellular mechanisms of the anabolic effect of intermittent PTH

Abstract

Intermittent administration of parathyroid hormone (PTH) stimulates bone formation by increasing osteoblast number, but the molecular and cellular mechanisms underlying this effect are not completely understood. In vitro and in vivo studies have shown that PTH directly activates survival signaling in osteoblasts; and that delay of osteoblast apoptosis is a major contributor to the increased osteoblast number, at least in mice. This effect requires Runx2-dependent expression of anti-apoptotic genes like Bcl-2. PTH also causes exit of replicating progenitors from the cell cycle by decreasing expression of cyclin D and increasing expression of several cyclin-dependent kinase inhibitors. Exit from the cell cycle may set the stage for pro-differentiating and pro-survival effects of locally produced growth factors and cytokines, the level and/or activity of which are known to be influenced by PTH. Observations from genetically modified mice suggest that the anabolic effect of intermittent PTH requires insulin-like growth factor-I (IGF-I), fibroblast growth factor-2 (FGF-2), and perhaps Wnts. Attenuation of the negative effects of PPAR gamma may also lead to increased osteoblast number. Daily injections of PTH may add to the pro-differentiating and pro-survival effects of locally produced PTH related protein (PTHrP). As a result, osteoblast number increases beyond that needed to replace the bone removed by osteoclasts during bone remodeling. The pleiotropic effects of intermittent PTH, each of which alone may increase osteoblast number, may explain why this therapy reverses bone loss in most osteoporotic individuals regardless of the underlying pathophysiology.

Figure 1. Proposed cellular mechanisms involved in the anabolic effect of intermittent PTH

The 3 stages of bone formation are described in the text. Intermittent PTH has been proposed to increase osteoblast number by (A) increasing the development of osteoblasts, (B) inhibiting osteoblast apoptosis, and (C) reactivating lining cells to resume their matrix synthesizing function.

Figure 2. PTH-stimulated survival signaling in osteoblasts

The upper panel depicts PTH-activated survival pathways, and the negative feedback on these pathways caused by stimulation of Runx2 degradation. The lower panel depicts the transient anti-apoptotic signaling and the changes in Runx2 that occur upon each injection of PTH. The net result is a temporary delay in osteoblast apoptosis. As injected PTH disappears from the circulation, Runx2 returns to basal levels and the cells are positioned to generate another episode of anti-apoptotic signaling in response to a subsequent injection. With sustained PTH elevation, on the other hand, the negative feedback pathway remains active, and further anti-apoptosis signaling is abrogated.

Figure 3. Actions of intermittent PTH on osteoblast progenitors

PTH exerts anti-mitotic effects on replicating osteoblast progenitors, and may also inhibit their apoptosis. The anti-mitotic effects may be necessary for differentiation in response to locally produced autocrine/paracrine growth factors regulated by PTH, as well as factors released from the bone matrix during bone resorption. PTH may also increase the number of osteoblast progenitors by preventing the differentiation of adipocytes from multipotential progenitors.