miR-23a/b clusters are not essential for the pathogenesis of osteoarthritis in mouse aging and post-traumatic models

Abstract

Osteoarthritis (OA), the most prevalent aging-related joint disease, is characterized by insufficient extracellular matrix synthesis and articular cartilage degradation and is caused by various risk factors including aging and traumatic injury. Most microRNAs (miRNAs) have been associated with pathogenesis of osteoarthritis (OA) using in vitro models. However, the role of many miRNAs in skeletal development and OA pathogenesis is uncharacterized in vivo using genetically modified mice. Here, we focused on miR-23–27–24 clusters. There are two paralogous miR-23–27–24 clusters: miR-23a-27a-24–2 (miR-23a cluster) and miR-23b-27b-24–1 (miR-23b cluster). Each miR-23a/b, miR-24, and miR-27a/b is thought to function coordinately and complementary to each other, and the role of each miR-23a/b, miR-24, and miR-27a/b in OA pathogenesis is still controversial. MiR-23a/b clusters are highly expressed in chondrocytes and the present study examined their role in OA. We analyzed miRNA expression in chondrocytes and investigated cartilage-specific miR-23a/b clusters knockout (Col2a1-Cre; miR-23a/bflox/flox: Cart-miR-23clus KO) mice and global miR-23a/b clusters knockout (CAG-Cre; miR-23a/bflox/flox: Glob-miR-23clus KO) mice. Knees of Cart- and Glob-miR-23a/b clusters KO mice were evaluated by histological grading systems for knee joint tissues using aging model (12 and/or 18 month-old) and surgically-induced OA model. miR-23a/b clusters were among the most highly expressed miRNAs in chondrocytes. Skeletal development of Cart- and Glob-miR-23clus KO mice was grossly normal although Glob-miR-23clus KO had reduced body weight, adipose tissue and bone density. In the aging model and surgically-induced OA model, Cart- and Glob-miR-23clus KO mice exhibited mild OA-like changes such as proteoglycan loss and cartilage fibrillation. However, the histological scores were not significantly different in terms of the severity of OA in Cart- and Glob-miR-23clus KO mice compared with control mice. Together, miR-23a/b clusters, composed of miR-23a/b, miR-24, miR-27a/b do not significantly contribute to OA pathogenesis.

Deficiency of MicroRNA-23-27-24 Clusters Exhibits the Impairment of Myelination in the Central Nervous System

“…Previous studies showed that the miR-23-27-24 cluster is expressed in the lung, skeletal muscle, and liver [ 18 ]. Our recent previous study demonstrated that the miR-23-27-24 cluster is expressed in these organs as well as in the CNS [ 28 ]. Since the miR-23-27-24 cluster is expressed in skeletal muscles, it could be argued that motor impairment upon miR-23-27-24 cluster deletion is possibly due to the loss of skeletal muscle function.…”

Myelin-Specific microRNA-23a/b Cluster Deletion Inhibits Myelination in the Central Nervous System during Postnatal Growth and Aging

“…Previous studies have reported the expression of miR-23a/b clusters in the liver, lungs, skeletal muscles, and CNS [14,18,19]. In this context, the present study assessed changes in the expression of these clusters in the organs of myelin-specific miR-23a/b cluster-deficient mice.…”

“…Genotyping was performed using genomic deoxyribonucleic acid extracted from the tail tip, as previously described [18,19]. The KO mice were specifically identified using PCR with the primers 5 ′ -GCA TTA CCG GTC GAT GCA ACG AGT GTA GAG-3 ′ and 5 ′ -GAG TGA ACG AAC CTG GTC GAA ATC AGT GCG-3 ′ .…”

“…In our previous study, mice with a global miR-23a/b cluster knockout (KO) from embryonic life, comprising miR-23a-27a-24-2 (miR-23a cluster) and miR-23b-27b-24-1 (miR-23b cluster), showed hypoplastic myelin sheath formation in the brain and spinal cord [14]. However, due to the widespread expression of miR-23a/b clusters in various tissues, including the lungs, skeletal muscle, liver, and CNS, studies using global miR-23a/b cluster KO mice have been unable to delineate tissue-specific mechanisms [18,19]. Moreover, the role of miR-23a/b clusters in postnatal growth and aging could not be evaluated, given the deficiency of miR-23a/b clusters from the developmental stage.…”