The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/12/1741/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 12, December 20, 1999 1741-1754

Original Article

Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of c-Fms and Receptor Activator of Nuclear Factor {kappa}B (RANK) Receptors

Fumio Araia,b, Takeshi Miyamotoa, Osamu Ohnedaa, Tomohisa Inadaa, Tetsuo Sudoc, Kenneth Braseld, Takashi Miyatab, Dirk M. Andersond, and Toshio Sudaa
a Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan
b Department of Periodontology, Meikai University School of Dentistry, Sakado 350-0248, Japan
c Basic Research Laboratories, Toray Industries, Incorporated, Kamakura 248-0036, Japan
d Department of Molecular Biology, Immunex Corporation, Seattle, Washington 98101-2936

Correspondence to: Toshio Suda, Dept. of Cell Differentiation, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan. Tel:81-96-373-5328 Fax:81-96-373-5332 E-mail:sudato{at}gpo.kumamoto-u.ac.jp.

Osteoclasts are terminally differentiated cells derived from hematopoietic stem cells. However, how their precursor cells diverge from macrophagic lineages is not known. We have identified early and late stages of osteoclastogenesis, in which precursor cells sequentially express c-Fms followed by receptor activator of nuclear factor {kappa}B (RANK), and have demonstrated that RANK expression in early-stage of precursor cells (c-Fms+RANK-) was stimulated by macrophage colony-stimulating factor (M-CSF). Although M-CSF and RANKL (ligand) induced commitment of late-stage precursor cells (c-Fms+RANK+) into osteoclasts, even late-stage precursors have the potential to differentiate into macrophages without RANKL. Pretreatment of precursors with M-CSF and delayed addition of RANKL showed that timing of RANK expression and subsequent binding of RANKL are critical for osteoclastogenesis. Thus, the RANK–RANKL system determines the osteoclast differentiation of bipotential precursors in the default pathway of macrophagic differentiation.

Key Words: osteoclastogenesis, commitment, macrophage, RANK ligand, M-CSF


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