Studies of the role of nf-κb in controlling osteoclast differentiation and bone loss

Increased osteoclast (OC) bone resorption and/or decreased osteoblast (OB) bone formation contribute to bone loss in osteoporosis and rheumatoid arthritis (RA). Findings of the basic and translational research presented in this thesis demonstrate a number of mechanisms by which cytokine-induced NF-κB activation controls bone resorption and formation: 1) Tumour necrosis factor-α (TNF) expands pool of OC precursors (OCPs) by promoting their proliferation through stimulation of the expression of macrophage colony stimulating factor (M-CSF) receptor, c-Fms, and switching M-CSF-induced resident (M2) to inflammatory (M1) macrophages with enhanced OC forming potential and increased production of inflammatory factors through induction of NF-κB RelB; 2) Similar to RANKL, TNF sequentially activates transcriptional factors NF-κB p50 and p52 followed by c-Fos and then NFATc1 to induce OC differentiation. However, TNF alone induces very limited OC differentiation. In contrast, it pre-activates OCPs to express cFos which cooperates with interleukin-1 (IL-1) produced by these OCPs in an autocrine mechanism by interacting with bone matrix to mediate the OC terminal differentiation and bone resorption from these pre-activated OCPs. 3) TNF-induced OC formation is independent of RANKL but it also induces NF-κB2 p100 to limit OC formation and bone resorption, and thus p100 deletion accelerates joint destruction and systemic bone loss in TNF-induced RA; 4) TNF receptor associated factor-3 (TRAF3) limits OC differentiation by negatively regulating non-canonical NF-κB activation and RANKL induces TRAF3 ubiquitination and lysosomal degradation to promote OC differentiation. Importantly, a lysosomal inhibitor that inhibits TRAF3 degradation prevents ovariectomy-induced bone loss; 5) RelB and Notch NICD bind RUNX2 to inhibit OB differentiation and RelB:p52 dimer association with NICD inhibit OB differentiation by enhancing the binding of RBPjκ to Hes1. These findings suggest that non-canonical NF- κB signaling could be targets to develop new therapies for RA or osteoporosis. For example 1) Agents that degrade TNF-induced RelB could block M1 macrophage differentiation to inhibit inflammation and joint destruction for the therapy of RA; 2)Agents that prevent p100 processing or TRAF3 degradation could inhibit bone resorption and also stimulate bone formation simultaneously for the therapy of osteoporosis.

‘State failure’ and the extraterritorial use of force in self-defence against non-state actors

The thesis is first and foremost the examination of the notion and consequences of ‘state failure’ in international law. The disputes surrounding criteria for creation and recognition of states pertain to efforts to analyse legal and factual issues unravelling throughout the continuing existence of states, as best evidenced by the ‘state failure’ phenomenon. It is argued that although the ‘statehood’ of failed states remains uncontested, their sovereignty is increasingly considered to be dependent on the existence of effective governments. The second part of this thesis focuses on the examinations of the legal consequences of the continuing existence of failed states in the context of jus ad bellum. Since the creation of the United Nations the ability of states to resort to armed force without violating what might be considered as the single most important norm of international law, has been considerably limited. State failure and increasing importance of non-state actors has become a greatly topical issue within recent years in both scholarship and the popular imagination. There have been important legal developments within international law, which have provoked much academic, and in particular, legal commentary. On one level, the thesis contributes to this commentary. Despite the fact that the international community continues to perpetuate a notion of ‘statehood’ which allows the state-centric system of international law to exist, when dealing with practical and political realities of state failure, international law may no longer consider external sovereignty of states as an undeniable entitlement to statehood. Accordingly, the main research question of this thesis is whether the implicit and explicit invocation of the state failure provides sufficient legal basis for the intervention in self-defence against non-state actors in located in failed states. It has been argued that state failure has a profound impact, the extent of which is yet to be fully explored, on the modern landscape of peace and security.