[Frontiers in Bioscience 16, 21-30, January 1, 2011]

Regulatory Mechanism of Osteoclastogenesis by RANKL and Wnt Signals

Naoyuki Takahashi1, Kazuhiro Maeda1,4, Akihiro Ishihara1,2, Shunsuke Uehara3, Yasuhiro Kobayashi1

1Institute for Oral Science, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan, 2Department of Periodontology, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan, 3Department of Biochemistry, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan, 4Department of Orthopaedic Surgery, Jikei University, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
2. Introduction
3. Regulation of osteoclast differentiation and function
3.1. M-CSF
3.2. RANKL
3.3. DC-STAMP
4. Signal transduction in osteoclastogenesis
4.1. NFATc1
4.2. Co-stimulatory ITAM signals
5. Wnt signalling pathways
5.1. Canonical and noncanonical Wnt signals
5.2. Role of canonical Wnt signals in bone resorption
5.3. Role of noncanonical Wnt signals in bone resorption
6. Conclusions
7. References

1. ABSTRACT

Osteoclasts develop from monocyte-macrophage lineage cells under the regulation of osteoblasts. Osteoblasts express two cytokines essential for osteoclastogenesis, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-B ligand (RANKL). Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor for RANKL, which inhibits the interaction between RANKL and RANK, a receptor of RANKL. Bone resorption-stimulating factors act on osteoblasts to regulate RANKL and OPG expression. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) is a master transcription factor for osteoclast differentiation. The immunoreceptor tyrosine-based activation motif (ITAM)-mediated signal was discovered as a co-stimulatory signal in RANKL-induced osteoclastogenesis. Wnt proteins activate two pathways: -catenin-dependent canonical and -catenin-independent noncanonical pathways. Wnt proteins promote differentiation of osteoblasts through the canonical pathway. The canonical pathway in osteoblasts also suppresses osteoclastogenesis through up-regulation of OPG expression and down-regulation of RANKL expression. In contrast, activation of the noncanonical pathway in osteoclast precursors enhances RANKL-induced osteoclastic differentiation. Thus, Wnt signals in osteoblasts and osteoclast precursors play important roles in osteoclastogenesis. This review summarizes the regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals.