Uncovering hidden pathways

An investigation into the pathway by which bone-remodeling cells differentiate has yielded information about an unexpected, parallel development pathway

As with any renovation project, skeletal growth and repair require a regulated balance between demolition and construction. These processes are mediated by two classes of cells: the osteoblasts that synthesize bone, and the osteoclasts that break it down.

Uncontrolled osteoclast production can have dire consequences for skeletal integrity, and a better understanding of the process by which osteoclasts differentiate from precursor cells could lead to better therapeutic strategies for treating bone diseases. One known trigger is the osteoclast differentiating factor RANKL, which induces fluctuations in intracellular calcium levels that activate additional signaling molecules responsible for osteoclast development.

Katsuhiko Mikoshiba's team at the RIKEN Brain Science Institute in Wako has focused much of their research on the IP3 receptors (IP3Rs), which are important regulators of cellular calcium trafficking, and Mikoshiba became interested in exploring a potential role for IP3R in RANKL-induced osteoclastogenesis.

In fact, his hunch was confirmed, and Yukiko Kuroda in Mikoshiba’s laboratory found that a specific subclass of IP3R is directly involved in mediating RANKL-induced calcium oscillation and inducing activation of the molecules required for osteoclast differentiation1. What they found next, however, was unexpected.

If calcium oscillation is an absolute requirement for differentiation, one would expect that precursor cells lacking IP3R would fail to form osteoclasts—but in fact, when IP3R-deficient precursor cells were cultured alongside osteoblasts, a considerable number of them successfully differentiated into osteoclasts.

Subsequent experiments confirmed that no calcium oscillation was taking place in these developing osteoclasts, providing evidence for a previously undiscovered, parallel pathway for differentiation (Fig. 1). This pathway was even observed in vivo, via experiments performed with mice lacking IP3R. “Before our report, it had been believed that RANKL-induced calcium oscillation [is] essential for osteoclast differentiation,” explains Kuroda and Mikoshiba. “We have demonstrated for the first time the existence of calcium oscillation-independent osteoclastogenesis.”

Precursor cells undergoing osteoclast formation via the calcium oscillation-independent pathway exhibit reduced efficiency in differentiation, suggesting that the two pathways may normally work together in concert, but respond differently to health-threatening disruptions. “Many situations are known to activate osteoclastogenesis in both physiological and pathological contexts,” says Mikoshiba. “We are speculating that both these two pathways contribute to osteoclastogenesis in normal bone development and that in some particular situations one pathway will be dominantly activated.” With this in mind, Mikoshiba’s group is now actively trying to sort out the mechanisms behind this novel pathway in order to better understand when and how it is typically activated in bone development.

Kuroda, Y., Hisatsune, C., Nakamura, T., Matsuo, K. & Mikoshiba, K. Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis. Proceedings of the National Academy of Sciences USA 105, 8643–8648 (2008).

The corresponding author for this highlight is based at the RIKEN Laboratory for Developmental Neurobiology

Published: 17 Oct 2008


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http://www.rikenresearch.riken.jp/research/556/ Link to article on RIKEN Research http://www.rikenresearch.riken.jp/research/556/image_1756.html Figure 1: Slides depicting differentiation of cultured bone precursor cells, illustrating how two pathways independently control osteoclastogenesis. Panels in the top row depict normal precursor cells, whereas the panels in the bottom row depict cells lacking IP3R—preventing intracellular calcium oscillations. Even without IP3R, cells can still differentiate into osteoclasts via a calcium oscillation-independent pathway when co-cultured with osteoblasts (lower right panel), although both pathways need to operate for normal levels of differentiation to occur (top right panel). When both pathways are inoperative, the cells fail to differentiate (bottom left). http://www.brain.riken.jp/en/k_mikoshiba.html RIKEN Laboratory for Developmental Neurobiology


Proceedings of the National Academy of Sciences USA 105, 8643–8648 (2008)