Abstract
Osteoclasts are large, myeloid-derived multinucleated cells primarily responsible for bone resorption.
Dysregulation of osteoclast differentiation can result in net bone resorption and is key to the pathophysiology of
osteoporosis, rheumatoid arthritis, and lytic bone metastasis. Despite substantial advances in the identification
of osteoclast master regulators, developing therapeutic interventions for pathologic osteoclasts has been
challenging due to off-target/side effects. Thus, we hypothesized that a better understanding of osteoclast-
specific regulation can directly lead to the development of novel osteoclast-specific therapeutic strategies to
prevent or halt the disease’s progression. Osteoclast gene transcription is highly organized and is understood
to be driven by enhancers. In order to identify osteoclast-specific epigenetic programs, we focused on super-
enhancers. Super-enhancers are clusters of enhancers that have been proposed to regulate key genes of
cellular identity and fate. We found 348 super-enhancers in human osteoclasts through genome-wide analysis
of differential transcriptional and epigenetic regulation. We also found that RANKL-regulated super-enhancers
are specific to osteoclasts but do not present in other types of cells. To increase the feasibility of targeting
these super-enhancers, we identified a new class of non-coding RNAs transcribed from super-enhancers
(named Oslincs) in human osteoclasts and provided evidence showing the role of Oslincs in gene expression
and osteoclastogenesis. In this application, we aim to characterize osteoclast-specific programs by
investigating Oslincs’ action and biogenesis in health and disease. Our specific aims are to 1) determine the
underlying mechanism of Oslincs’ function, 2) elucidate the mechanisms by which the expression of Oslincs is
regulated, and 3) identify Oslincs that are differentially regulated between healthy controls and patients with
rheumatoid arthritis (RA). We anticipate that the new information generated by this proposal will illuminate
osteoclast-specific regulation and allow us to explore the implementation of novel, targeted therapeutic
approaches for ameliorating the course of pathological bone loss.