The Regulatory Mechanisms of Osteoclasts

Abstract Osteoclasts are multinucleated cells primarily responsible for bone resorption. The dysregulation of osteoclast differentiation can result in excessive bone resorption and is key to the pathophysiology of bone diseases, such as osteoporosis, rheumatoid arthritis, and lytic bone metastasis. Despite substantial advances in anti- resorptive therapies, developing therapeutic interventions for pathologic osteoclasts has been challenging due to the occurrence of rare but significant side effects, drug tolerance, and patient compliance. Our overarching hypothesis is that these unwanted effects of antiresorptive therapies can be lowered by cell-specific targeting. Osteoclasts are long-live cells that continuously acquire new nuclei by fusion with circulating osteoclast precursor cells (cOCPs) and are recycled through the fusion and fission cycle of osteomorphs. This new concept of long-lived osteoclasts highlights the important role of cOCPs in the management of osteoclasts and supports that cOCPs can serve as an osteoclast-specific target. We have identified and characterized human cOCPs and found a positive association between cOCPs and osteoporosis. Sorted cOCPs from the blood circulation have a higher osteoclastogenic potential than other myeloid cells and effectively differentiate into osteoclasts. Moreover, cOCPs exhibit distinct morphology and transcriptomic signatures compared to other myeloid cells. cOCPs are inversely correlated with bone density and are positively associated with serum CTX1 in postmenopausal women. Intriguingly, we found that nuclei in multinuclear osteoclasts are heterogeneous, and ‘new vs old nuclei’ show distinct gene expression profiles. We hypothesize that cOCPs reflect the changes in bone environment and that newly incorporated nuclei from cOCPs regulate osteoclast activity. In this application, we aim to determine the mechanisms underlying the regulation of cOCPs. Our specific aims are 1) to elucidate the underlying mechanism by which cOCPs are regulated and 2) to determine the mechanism governing the function of cOCPs. We anticipate that the proposed study will provide new insights into the regulatory mechanism of osteoclast formation and enable us to investigate osteoclast-specific regulation, ultimately leading to improved management of the course of pathological bone loss.