NIK stabilization in osteoclasts results in osteoporosis and enhanced inflammatory osteolysis.

BACKGROUND: Maintenance of healthy bone requires the balanced activities of osteoclasts (OCs), which resorb bone, and osteoblasts, which build bone. Disproportionate action of OCs is responsible for the bone loss associated with postmenopausal osteoporosis and rheumatoid arthritis. NF-κB inducing kinase (NIK) controls activation of the alternative NF-κB pathway, a critical pathway for OC differentiation. Under basal conditions, TRAF3-mediated NIK degradation prevents downstream signaling, and disruption of the NIK:TRAF3 interaction stabilizes NIK leading to constitutive activation of the alternative NF-κB pathway. METHODOLOGY/PRINCIPAL FINDINGS: Using transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), we now find that alternative NF-κB activation enhances not only OC differentiation but also OC function. Activating NT3 with either lysozyme M Cre or cathepsinK Cre causes high turnover osteoporosis with increased activity of OCs and osteoblasts. In vitro, NT3-expressing precursors form OCs more quickly and at lower doses of RANKL. When cultured on bone, they exhibit larger actin rings and increased resorptive activity. OC-specific NT3 transgenic mice also have an exaggerated osteolytic response to the serum transfer model of arthritis. CONCLUSIONS: Constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli.

PLCgamma2: where bone and immune cells find their common ground.

Identifying common signaling pathways to bone and immune system may lead to better therapeutic approaches in diseases such as inflammatory arthritis. In this context, PLCgamma2 seems to be a promising target. PLCgamma2 modulates bone homeostasis by affecting osteoclast recruitment and function. Via its catalytic activity and the adapter domains, PLCgamma2 controls RANKL and alphavbeta3 integrin-dependent signaling pathways in the resorbing cell. Thus, mice lacking PLCgamma2 are osteopetrotic. PLCgamma2 also regulates neutrophil degranulation after beta2 integrin-dependent attachment. Indeed PLCgamma2(-/-) mice are protected from K/BxN serum transfer arthritis, which is known to require neutrophil activation. These studies position PLCgamma2 as a critical regulator of the cellular and molecular mechanisms occurring in bone and immune cells during autoimmune inflammation.

Oxytocin is an anabolic bone hormone.

We report that oxytocin (OT), a primitive neurohypophyseal hormone, hitherto thought solely to modulate lactation and social bonding, is a direct regulator of bone mass. Deletion of OT or the OT receptor (Oxtr) in male or female mice causes osteoporosis resulting from reduced bone formation. Consistent with low bone formation, OT stimulates the differentiation of osteoblasts to a mineralizing phenotype by causing the up-regulation of BMP-2, which in turn controls Schnurri-2 and 3, Osterix, and ATF-4 expression. In contrast, OT has dual effects on the osteoclast. It stimulates osteoclast formation both directly, by activating NF-kappaB and MAP kinase signaling, and indirectly through the up-regulation of RANK-L. On the other hand, OT inhibits bone resorption by mature osteoclasts by triggering cytosolic Ca(2+) release and NO synthesis. Together, the complementary genetic and pharmacologic approaches reveal OT as a novel anabolic regulator of bone mass, with potential implications for osteoporosis therapy.