The earlier expression of occur after commitment to the OC lineage. In addition to finding increased OC differentiation, our in vitro experiments indicated that NIK activation also enhances the resorptive capacity of each OC. When we plated equal Masitinib msds numbers of preosteoclasts on bone at high doses of RANKL, which further normalizes the numbers of OCs formed, we still saw a large increase in bone resorption by NT3-expressing OCs. Intriguingly, actin rings were 3-fold larger in area in NT3.catK OCs compared to Ctl OCs, extending almost to the cell edge. Preliminary experiments suggest that even on plastic, NT3 drives increased expression of a subset of cytoskeleton-associated proteins. Although there are a number of suggestions in the literature that the cytoskeleton can alter signaling pathways including NF-kB, there are no direct studies indicating that the alternative pathway can regulate the cytoskeleton. Once the actin ring and sealing zone are formed, the OC must secrete enzymes and acid to accomplish bone resorption. Our observation that NT3 OCs are highly efficient bone resorbers may indicate NIK also plays a role in these processes. Exposure of OC precursors to RANKL causes NIK-dependent processing of p100 to p52, an event necessary for OC differentiation in vitro. Expression of the stabilized form of NIK, NT3, increased this processing event and enhanced osteoclastogenesis. However, we do not know whether this traditional role for NIK is responsible for all of the observed stimulatory effects on OCs. Ablation of NIK causes accumulation of p100 which inhibits classical NF-kB signaling by binding p65, although this does not contribute significantly to the observed block in OC differentiation. Nevertheless, activation of the classical pathway by NT3 could contribute to increased OC numbers, either by supporting the differentiation program or inhibiting apoptosis. In other cell types, NIK has been shown to impact STAT3 signaling and ERK activation, and activation of these pathways could impact the OC as well. Further studies will be required to determine all of the pathways impacted by NIK stabilization in the OC. The most common form of systemic bone loss is postmenopausal osteoporosis caused by estrogen deficiency. In the early phases of this disease, the activity of both OCs and OBs is increased leading to high bone turnover. However, bone resorption and formation are not balanced, and the net effect is bone loss, primarily in the trabeculae. Most studies have focused on stimulation of OCs as the primary event. In physiologic bone remodeling, the differentiation and activity of OBs is coupled to that of OCs via as yet incompletely defined factors, and in early osteoporosis the OB activation is also thought to be secondary to the OC. Analysis of NT3.catK mice demonstrated that, at baseline, the number of OCs was increased, as were serum levels of CTX, a marker of OC activity, indicating that bone resorption was increased.