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.
