Role of EP₃ and EP₄ Prostaglandin Receptors in Reorganization of the Cytoskeleton in Mature Human Osteoclasts

PATRICE SARRAZIN, JOSETTE A. HACKETT, ISABELLE FORTIER, MAXIME A. GALLANT, and ARTUR J. de BRUM-FERNANDES

ABSTRACT.

Objective. Osteoclasts are central to the pathophysiology of several bone diseases. Prostaglandin E₂ (PGE₂) is well known to influence osteoclasts indirectly, but its direct action on osteoclasts is still controversial and the relevant receptors are unknown. We investigated the distribution and function of EP receptors in human mature osteoclasts.

Methods. Osteoclasts were extracted from femurs and tibias of human fetuses obtained from legal abortions. In situ hybridization and immunohistochemistry were used to detect the presence of EP₁, EP₂, EP₃, and EP₄ receptors on these cells. Actin staining and fluorescent microscopy were used to detect the effects of receptor activation on the cytoskeleton.

Results. Only EP₃ and EP₄ receptors were detected at the RNA and protein level in osteoclasts. These receptors were functional: PGE₂ decreased the number of osteoclasts presenting an actin ring; 11-deoxy-PGE₁, an EP₂ and EP₄ agonist, also decreased the number of tartrate-resistant acid phosphatase-positive cells with an actin ring; sulprostone, an EP₃-specific agonist, had no effect on this variable but increased the number of cells with lamellipodia.

Conclusion. Mature human osteoclasts present 2 subtypes of EP receptors, namely EP₃ and EP₄, that mediate different actions of PGE₂ on these cells: activation of the EP₄ receptors inhibits actin ring formation and activation of the EP₃ receptors increases the number of lamellipodia. Activation or inhibition of these receptors by specific agents could be used to study and influence osteoclast function. (J Rheumatol 2004;31:1598-606)

Key Indexing Terms:

PROSTAGLANDINS
BONE
OSTEOCLASTS

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From the Division of Rheumatology, Department of Medicine, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.

Supported by grants from the Medical Research Council of Canada (MT15024), The Arthritis Society (95041), and the FCAR/FRSQ.

P. Sarrazin, PhD; J. Hackett, BSc; I. Fortier, MSc; M. Gallant, BSc; A. de Brum-Fernandes, MD, PhD.

Address reprint requests to Dr. A.J. de Brum-Fernandes, Division of Rheumatology, Faculty of Medicine, Université de Sherbrooke, 3001 12th Avenue Nord, Sherbrooke, Québec J1H 5N4. E-mail: Artur.Fernandes@USherbrooke.ca

Submitted October 3, 2003; revision accepted February 5, 2004.

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