Using mice expressing this mutant NIK allele in OC lineage cells, we describe the effects of constitutive NIK activation in OCs both in vivo and in vitro. We find that NIKDT3 transgenic mice are osteoporotic at baseline, and are much more sensitive to inflammatory osteolysis than nontransgenic littermates using the serum transfer model of arthritis. In vitro, NIKDT3 drives more robust OC differentiation and generates more active OCs characterized by an enlarged actin ring, indicating that the alternative NF-kB pathway controls not only OC differentiation but also resorptive activity. Thus, inhibition of NIK is a promising therapeutic Screening Libraries inhibitor strategy for preventing pathological bone loss, while activation of NIK, such as might occur with cIAP antagonists, may accelerate bone loss due to OC activation. Unlike the classical NF-kB pathway, which is activated by a wide array of inflammatory and infectious stimuli, the alternative NF-kB pathway is activated by only a small subset of cytokines, including RANKL, Ltb, CD40L and BAFF. Knockouts of various alternative pathway components have demonstrated roles in maturation of B cells and induction of TH17 cells, as well as differentiation of osteoclasts, suggesting that this pathway might be a relatively specific target for autoimmune diseases, especially those associated with bone loss. The stability of NIK is one of the key control points for activation of the alternative NF-kB pathway. Recent studies of mutations in multiple myelomas revealed that NIK, or more frequently proteins such as TRAF3 and cIAPs that control NIK degradation, are targets for mutation in these tumors. This observation led to generation of transgenic mice expressing a stabilized form of NIK, using a tissue-specific Cre-mediated activation approach, which results in tissue-specific constitutive alternative pathway activation. By expressing this NT3 transgene in the OC lineage, we now describe the effects of NIK activation on bone homeostasis and inflammatory bone loss. In order to express NT3 in OCs, we utilized two Cre transgenic lines that have previously been shown to delete floxed alleles in this lineage. LysM-Cre mediates deletion in neutrophils, macrophages, and OCs, while CatK-Cre is more specific to the OC lineage, deleting at the preosteoclast stage. We found that both NT3.lysM and NT3.catK mice had severe osteoporosis at 8 weeks of age, with an approximate 50% loss in trabecular bone volume. In vitro, osteoclastogenesis occurred at lower doses of RANKL in both NT3.lysM and NT3.catK BMMs, even though NT3.catK BMMs did not show expression of NT3 until they had been cultured in RANKL for 2 days. Nevertheless, even in low doses of RANKL, only an additional 2 days were sufficient for full OC differentiation in NT3.catK cells. Overall, NT3.catK BMMs differentiated more quickly and at lower doses of RANKL than Ctl BMMs, and expressed higher levels of OC differentiation markers NFATc1, b3 integrin, DCStamp and calcitonin receptor.