The Therapeutic Potential of MicroRNAs as Orthobiologics for Skeletal Fractures

Abstract

The repair of a fractured bone is critical to the well‐being of humans. Failure of the repair process to proceed normally can lead to complicated fractures, exemplified by either a delay in union or a complete nonunion. Both of these conditions lead to pain, the possibility of additional surgery, and impairment of life quality. Additionally, work productivity decreases, income is reduced, and treatment costs increase, resulting in financial hardship. Thus, developing effective treatments for these difficult fractures or even accelerating the normal physiological repair process is warranted. Accumulating evidence shows that microRNAs (miRNAs), small noncoding RNAs, can serve as key regulatory molecules of fracture repair. In this review, a brief description of the fracture repair process and miRNA biogenesis is presented, as well as a summary of our current knowledge of the involvement of miRNAs in physiological fracture repair, osteoporotic fractures, and bone defect healing. Further, miRNA polymorphisms associated with fractures, miRNA presence in exosomes, and miRNAs as potential therapeutic orthobiologics are also discussed. This is a timely review as several miRNA‐based therapeutics have recently entered clinical trials for nonskeletal applications and thus it is incumbent upon bone researchers to explore whether miRNAs can become the next class of orthobiologics for the treatment of skeletal fractures.

Osteoprotective Roles of Green Tea Catechins

“…MiRNAs are small non-coding endogenous RNA molecules (around 19–25 nucleotides in length), which regulate post-transcriptional gene expression [ 72 , 73 , 74 , 75 , 76 ]. Five miRNAs (miR-21-5p, miR-24-3p, miR-93-5p, miR-100-5p, and miR-125b-5p) were found also significantly upregulated in bone tissue from osteoporotic patients compared to controls [ 77 ].…”

The Role of Exosomes in Bone Remodeling: Implications for Bone Physiology and Disease

“…A multitude of miRNAs are deregulated in osteoporosis in a cell-free, vesicle-free circulating form [83]. However, these are not readily comparable with the exosomal miRNA cargo; some are not consistently up- or downregulated in animal models of osteoporotic fractures in their free circulating form (miR-140-3p, miR-214), while others seem to promote both osteoclastogenesis and osteoblast differentiation in their exosomal form (miR-148a, miR-218) [84]. Nonetheless, both free and exosomal miR-29b-3p seem to enhance mouse fracture healing [84].…”

“…However, these are not readily comparable with the exosomal miRNA cargo; some are not consistently up- or downregulated in animal models of osteoporotic fractures in their free circulating form (miR-140-3p, miR-214), while others seem to promote both osteoclastogenesis and osteoblast differentiation in their exosomal form (miR-148a, miR-218) [84]. Nonetheless, both free and exosomal miR-29b-3p seem to enhance mouse fracture healing [84]. miRNA-21, which has been found upregulated in circulating exosomes of osteoporotic individuals, has an antiosteogenic impact, in that it inhibits SMAD7 protein with a subsequent downregulation of ALP , OCN , and RUNX2 [85].…”

miR‑205 regulates bone turnover in elderly female patients with type 2 diabetes mellitus through targeted inhibition of Runx2

“…Microribonucleic acids (microRNAs or miRs) are a type of single-stranded, non-coding and small-molecule RNAs approximately 18-25 nucleotides in length, which are involved in the occurrence and progression of various diseases ( 7 , 8 ). It has been reported that some miRs can participate in bone turnover, bone metabolism and bone development, thereby regulating the occurrence and progression of OP ( 9-11 ).…”