Therapeutic Potentials of a New Long Noncoding RNA in Diabetic Bone Wound Repair

Patients with type 2 diabetes (T2D) have substantially higher incidence of bone disorders, including as much as a 64% greater risk of fracture as compared to those without T2D. High blood glucose levels adversely alter bone cell functions, causing decreased bone formation and delayed wound healing with poor quality

tissue repair. Therefore, diabetic bone disease (DBD) is a serious health concern for more than 40 million people in the US and 370 million in the world currently afflicted with T2D. Current treatments for DBD include anti-resorptive drugs, selective estrogen receptor modulators, and anabolic (bone-forming) drugs. However,

these drugs target either the bone-formation or bone-resorption pathway, not both. Moreover, these drugs have little direct effect on diabetic hyperglycemia, a major root cause of T2D bone disorders. Furthermore, recent data indicate some anti-diabetic drugs have side effects that actually increase fracture risk in T2D. Therefore,

developing a safe and effective method to prevent DBD and restore and regenerate lost bone tissue in diabetics is critically important. Long noncoding RNAs (lncRNAs) are a family of non-protein-coding transcripts with length longer than 200 nucleotides. Emerging evidence suggests that lncRNAs play important roles in gene expression

and are involved the pathogenesis of many human diseases. Currently, there are over 60 clinical trials using lncRNAs as a remedy. Our laboratory has recently identified and initially characterized a specific lncRNA that promotes osteogenesis and inhibits adipogenesis in diabetes. It can recruit KDM6B and KDM4B and influence

the histone methylation of relevant genes. Its deficiency causes bone abnormalities and retards bone regeneration and delays wound healing in mouse models. This newly discovered lncRNA is therefore coined “lncR-DBD”, suggesting its potential roles in targeting the pathophysiology of diabetic bone disease. We have

successfully generated a lncR-DBD gene knockout mouse line which will enable us to further dissect the biological function of this new lncRNA. Aim 1 will determine the cellular localization of lncR-DBD and explore the epigenetic pathways using the state-of-the-art approaches; Aim 2 will define the mechanisms and alterations

in bone phenotype in lncR-DBD knockout mice; Aim 3 will use a novel nanohydrogel delivery system to investigate the therapeutic effects of lncR-DBD on bone wound repair and fracture healing in diabetic mice. The outcome of our study will provide a paradigm shift in current understanding of the pathophysiology of DBD and

have a significant impact on the future treatment of this epidemic disease. Firstly, building on our preliminary findings that lncR-DBD plays a pivotal role in bone metabolism, this project will further reveal novel epigenetic mechanisms of DBD. Secondly, we will decipher the pathways of lncR-DBD modulating genes in the diabetic

microenvironment, which will lead to discovery of new therapeutic targets. Finally, we will deliver the lncR-DBD mimics using a novel nanohydrogel system as a safe, effective means for lncRNA-based therapy. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies.