Early postnatal ablation of the microRNA-processing enzyme, Drosha, causes chondrocyte death and impairs the structural integrity of the articular cartilage

Abstract

SUMMARY Objective In growth plate chondrocytes, loss of Dicer, a microRNA (miRNA)-processing enzyme, causes defects in proliferation and differentiation, leading to a lethal skeletal dysplasia. However roles of miRNAs in articular chondrocytes have not been defined in vivo. To investigate the role of miRNAs in articular chondrocytes and to explore the possibility of generating a novel mouse osteoarthritis (OA) model caused by intrinsic cellular dysfunction, we ablated Drosha, another essential enzyme for miRNA biogenesis, exclusively in articular chondrocytes of postnatal mice. Design First, to confirm that the essential role of miRNAs in skeletal development, we ablated the miRNA biogenesis pathway by deleting Drosha or DGCR8 in growth plate chondrocytes. Next, to investigate the role of miRNAs in articular cartilage, we deleted Drosha using Prg4-CreERT transgenic mice expressing a tamoxifen-activated Cre recombinase (CreERT) exclusively in articular chondrocytes. Tamoxifen was injected at postnatal days, 7, 14, 21, and 28 to ablate Drosha. Results Deletion of Drosha or DGCR8 in growth plate chondrocytes caused a lethal skeletal defect similar to that of Dicer deletion, confirming the essential role of miRNAs in normal skeletogenesis. Early postnatal Drosha deletion in articular chondrocytes significantly increased cell death and decreased Safranin-O staining. Mild OA-like changes, including surface erosion and cleft formation, were found in male mice at 6 months of age; however such changes in females were not observed even at 9 months of age. Conclusions Early postnatal Drosha deficiency induces articular chondrocyte death and can cause a mild OA-like pathology.

MicroRNAs and Autophagy: Fine Players in the Control of Chondrocyte Homeostatic Activities in Osteoarthritis

“…Since DICER composes the miR processor, this finding unveils the fundamental role of miRs in chondrogenesis and bone development [33]. The latter has been further confirmed by similar results achieved in mice with DROSHA and DGCR-8-deficient COL-2 α 1-expressing cells [34]. …”

The Role of MicroRNAs and Their Targets in Osteoarthritis

“…Furthermore, Drosha and DGCR8 deficiency in Col2α1-expressing cells also showed abnormal skeletal development similar to that seen in the Dicer-deficient mice [85]. Interestingly, mice in which Drosha deletion was induced postnatally in articular cartilage Prg4-expressing cells develop mild-OA naturally due to increased chondrocyte death and decreased extracellular matrix production [85]. Taken together this suggests that dysregulation of miRNAs and miRNA processing enzymes may be contributory in the development of OA pathology.…”

“…For example, Dicer deficiency in Col2α1-expressing cells leads to early postnatal lethality and reveals abnormal skeletal growth and development due to a reduction of proliferating chondrocytes [84]. Furthermore, Drosha and DGCR8 deficiency in Col2α1-expressing cells also showed abnormal skeletal development similar to that seen in the Dicer-deficient mice [85]. Interestingly, mice in which Drosha deletion was induced postnatally in articular cartilage Prg4-expressing cells develop mild-OA naturally due to increased chondrocyte death and decreased extracellular matrix production [85].…”

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

“…The miRNA–RISC complex mediates the degradation of specific mRNA targets and/or the repression of mRNA translation via interactions with the 3′ untranslated regions (UTRs) that are partially sequence‐specific (Jovanovic & Hengartner, 2006). Postnatal Drosha deficiency induces articular chondrocyte death and causes a mild OA‐like pathology (Kobayashi et al., 2015), and miR‐140 is involved in the pathogenesis of osteoarthritis by regulating ADAMTS5 (Araldi & Schipani, 2010). These findings suggest that miRNAs play a critical role in cartilage homeostasis.…”