Figure 1. Osteoclast differentiation is stimulated by TRANCE/TNFSF11 via its receptor, RANK/TNFRSF11, expressed on pre-osteoclast cells. However, under normal physiological conditions, these signals are not sufficient and new evidence implies the existence of other mediators. A new co-stimulatory pathway has been described in which osteoclasts must also be co-stimulated via their TREM-2/DAP12 and/or OSCAR/Fc R gamma receptor complexes by as yet unknown ligands in order to achieve mature osteoclast development and associated bone resorptive capacity. [Note: figure adapted from Baron, R. (2004) Nat. Med. 10:458.]

It has been known for some time that osteoclasts are derived from the myeloid hematopoietic lineage and that the development of osteoclast precursors requires contact with osteoblasts or bone marrow stromal cells. A few years ago, the mediator of this effect was finally identified as TRANCE/TNFSF11. TRANCE is secreted from osteoblasts and stromal cells and binds its receptor RANK/TNFRSF11 on the surface of hematopoietic precursors to drive them into an osteoclast fate. The TRANCE/RANK system also functions to activate mature osteoclasts, thereby initiating bone resorption^1,2 (Figure 1).

Since the development of this TRANCE/RANK model of osteoclastogenesis, several pieces of evidence have been presented that imply the involvement of other critical mediators in this process.³ In particular, loss-of-function mutations in TREM-2 and DAP12 receptors result in Nasu-Hakola disease, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, an extremely rare, recessive disease characterized by bone cysts and presenile dementia. In vitro, peripheral blood mononuclear cells from Nasu-Hakola patients fail to differentiate into mature osteoclasts, instead forming masses of immature osteoclasts with poor bone resorptive function.^4,5 Further, DAP12 knockout mice display Nasu-Hakola disease-like osteopetrosis symptoms and similar arrested development of mature osteoclasts resulting in reduced bone resorption.⁶ Another important mediator of osteoclastogenesis appears to be the osteoclast-associated receptor (OSCAR). OSCAR is stimulated via interactions with unknown factors derived from osteoblasts to elicit mature osteoclast differentiation. Introduction of a soluble form of OSCAR into this co-culture system inhibits both osteoclast maturation and bone resorption.⁷

A new study by Koga et al. describes a more complex model of osteoclastogenesis in which co-stimulatory mechanisms play an important role in fine tuning osteoclast development.⁸ Both TREM-2 and OSCAR are single-pass transmembrane orphan receptors that associate with immunoreceptor tyrosine activation motif (ITAM)-bearing adaptor proteins to achieve signaling. In the case of TREM-2, this adaptor protein is DAP12. The TREM-2/DAP12 heteromeric receptor complex has been described as co-stimulating to myeloid cells in a number of contexts.^3,9 Koga et al. identify Fc R gamma as the ITAM-containing adaptor protein that associates with OSCAR. While the ligands for both TREM-2 and OSCAR remain unidentified, Koga et al. confirm that these ligands are provided by osteoblasts. In a series of knockout studies, they illustrate the importance of these co-stimulatory mechanisms for osteoclast maturation. DAP12^-/- mice and Fc R gamma^-/- mice display only mild osteopetrosis while DAP12^-/- Fc R gamma^-/- double-knockout mice have a much more severe phenotype and very few osteoclast cells. They also demonstrate the involvement of the DAP12 and Fc R gamma ITAM motifs in downstream signaling events. Finally, Koga et al. show that while RANK, TREM-2, and OSCAR-mediated signals are necessary, none are sufficient for appropriate osteoclast maturation under physiological conditions.⁸

The exact pathophysiology of Nasu-Hakola disease remains unknown. However, these new findings provide some clues as to its molecular mechanism and hopefully enhance the search for potential therapies.³ Even more exciting is the prospect of new insights these studies provide into potential therapeutic targets for the millions of elderly individuals living with osteoporosis. As osteoporosis results from exaggerated osteoclast bone resorption activity, targeting osteoclast maturation may be a possibility for osteoporosis therapy. One drawback is that TRANCE, RANK, TREM-2, and DAP12 are important immune system modulators as well. However, OSCAR has only been observed thus far in osteoclasts and may represent a good bone-specific therapeutic target for osteoporosis.⁷

References

1. Boyle, W.J. et al. (2003) Nature 423:337.
2. Teitelbaum, S.L. & F.P. Ross (2003) Nat. Rev. Genet. 4:638.
3. Baron, R. (2004) Nat. Med. 10:458.
4. Cella, M. et al. (2003) J. Exp. Med. 198:645.
5. Paloneva, J. et al. (2003) J. Exp. Med. 198:669.
6. Kaifu, T. et al. (2003) J. Clin. Invest. 111:323.
7. Kim, N. et al. (2002) J. Exp. Med. 195:201.
8. Koga, T. et al. (2004) Nature 428:758.
9. Aoki, N. et al. (2003) Curr. Pharm. Des. 9:7.