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Bone density and structure is maintained through a balance of bone resorption by osteoclasts and bone deposition by osteoblasts. The combination of simultaneous resorption and deposition creates continual remodeling of bone while excess osteoclast activity leads to an imbalance and a loss of bone density, causing osteoporosis. RANK (receptor activator of NF-kB ligand) is a receptor in the TNF receptor gene family that is involved in osteoclast differentiation. RANK-ligand, also called osteoprotegerin-ligand, binds to RANK, induces receptor dimerization, and activates downstream signaling. Osteoprotegerin is a decoy receptor for RANK-ligand that suppresses osteoclast activity and bone remodeling, helping to maintain balanced bone remodeling. RANK-ligand and osteoprotegerin are produced by osteoblasts and some factors regulate osteoclast activity indirectly through their action on the expression of these factors by osteoblasts. Binding of RANK-ligand to RANK activates signaling through TRAF-6. TRAF-6 induces several downstream signaling events, including activation of NF-kB, c-Fos and the kinase JNK1. Jnk-1 activation contributes to fos activation by RANK-ligand and may be involved in the modulation of RANK-ligand by other factors such as estrogen. Mice lacking the c-Fos gene have overly dense bone and decreased bone resorption due to reduced osteoclast differentiation, indicating that c-Fos is an important mediator of osteoclast differentiation. One of the results of c-Fos induction is transcriptional activation of interferon-beta. Interferon-beta binds to its receptor on neighboring osteoclast precursor cells to block RANK-ligand signaling and down-regulate c-Fos expression, inhibiting further osteoclast differentiation. Mice lacking interferon-beta or the interferon-beta receptor lose bone due to uncontrolled osteoclast activity, demonstrating the importance of this mechanism in vivo. Interferon-beta signaling could be used as a mechanism to prevent osteoporosis and other conditions involving excessive osteoclast resorption of bone. (This definition may be outdated - see the DesignNote.)
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