Parathyroid Hormone Stimulates Osteoblastic Expression of MCP-1 to Recruit and Increase the Fusion of Pre/Osteoclasts

Nicola C. Partridge,Marika Bergenstock,Deborah V. Novack,Ling Qin,Laura M. Bevelock,Xin Li

doi:10.1074/jbc.m611781200

Abstract

The clinical findings that alendronate blunted the anabolic effect of human parathyroid hormone (PTH) on bone formation suggest that active resorption is involved and enhances the anabolic effect. PTH signals via its receptor on the osteoblast membrane, and osteoclasts are impacted indirectly via the products of osteoblasts. Microarray with RNA from rats injected with human PTH or vehicle showed a strong association between the stimulation of monocyte chemoattractant protein-1 (MCP-1) and the anabolic effects of PTH. PTH rapidly and dramatically stimulated MCP-1 mRNA in the femora of rats receiving daily injections of PTH or in primary osteoblastic and UMR 106-01 cells. The stimulation of MCP-1 mRNA was dose-dependent and a primary response to PTH signaling via the cAMP-dependent protein kinase pathway in vitro. Studies with the mouse monocyte cell line RAW 264.7 and mouse bone marrow proved that osteoblastic MCP-1 can potently recruit osteoclast monocyte precursors and facilitate receptor activator of NF-kappaB ligand-induced osteoclastogenesis and, in particular, enhanced fusion. Our model suggests that PTH-induced osteoblastic expression of MCP-1 is involved in recruitment and differentiation at the stage of multinucleation of osteoclast precursors. This information provides a rationale for increased osteoclast activity in the anabolic effects of PTH in addition to receptor activator of NF-kappaB ligand stimulation to initiate greater bone remodeling.

Highlights

The fold simulation of monocyte chemoattractant protein-1 (MCP-1) mRNA level kept increasing with longer parathyroid hormone (PTH) treatment resulting in an increase of more than 200-fold with 14 daily intermittent injections of PTH
In the PTH catabolic treatment model where hPTH-(1–34) was continuously infused into rats subcutaneously, the MCP-1 mRNA level was significantly increased in this region of bone at 6 h and 6 and 14 days but was never greater than 2.5-fold of the vehicle controls (Fig. 1B)
PTH increases bone formation and promotes bone remodeling [28]. Both clinical and animal studies have shown that bisphosphonates, inhibitors of bone resorption, can blunt the anabolic response to PTH, suggesting that active bone resorption enhances the anabolic actions of PTH [1,2,3]

Summary

Introduction

This hypothesis provides a rationale for increased osteoclast activity in the anabolic effect of PTH, apart from RANKL stimulation, to initiate greater bone remodeling in a transient time-dependent fashion. In the PTH catabolic treatment model where hPTH-(1–34) was continuously infused into rats subcutaneously, the MCP-1 mRNA level was significantly increased in this region of bone at 6 h and 6 and 14 days but was never greater than 2.5-fold of the vehicle controls (Fig. 1B).

Results

Conclusion