Osteoclast disease, such as Paget’s disease of the bone and osteoporosis, are pathological conditions of excessive bone resportion caused by disproportionate generation or over-activation of osteoclasts. They represent some of the most common chronic diseases that result in morbidity and disability in the elderly population with an estimation of more than 60 million people in the US currently affected with osteoclast diseases. My dissertation research focuses on studying the role of autophagy machinery in osteoclast differentiation and osteoclast disease pathogenesis.

In the second chapter, we investigate the role autophagy receptor Optineurin (OPTN) in the pathogenesis of Paget’s disease of the bone (PDB). We identify that OPTN acts as an intrinsic negative modulator for osteoclast development, as it restrains osteoclast differentiation in vitro and protects against the development of PDB in vivo. While the absence of OPTN results in a defective type I interferon responses in osteoclasts, exogenous supplementations of recombinant IFNβ completely reverse the hyperactivity observed in OPTN deficient osteoclasts. Therefore, we propose that IFNβ could serve a novel pharmacotherapy for PDB.

In the third chapter, we investigate the role of autophagy machinery in osteoclast differentiation. We reveal that certain upstream autophagy core proteins, such Beclin-1, VPS34, ATG14 and FIP200 are required for osteoclast development, which seems to be dispensable of autophagic flux. Moreover, we uncovered the noncanonical roles of autophagy protein Beclin-1 in osteoclast differentiation – nuclear Beclin-1 protects against DNA damages and cell death to maintain sufficient noncanonical NF-kB responses during osteoclastogenesis. Since mice with myeloid restricted Becn1 deficiency exhibit insignificant age-related bone loss, Beclin1 may be a novel therapeutic target for osteoporosis.

Taken together, my research adds knowledge to our current understanding of osteoclast development - the entire autophagy pathway is instrumental for osteoclast differentiation, through different components exert different control over the differentiation process. Targeting the autophagy and its effector pathways may be a novel anti-resorptive regimen for patients with osteoclast disease, and may potential benefit them in a multifaceted way