Abstract
Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains unknown. MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis pathogenesis. We have found that mechanical loading up-regulated microRNA miR-365 in growth plate chondrocytes, which promotes chondrocyte differentiation. Here, we explored the role of the mechanical responsive microRNA miR-365 in pathogenesis of osteoarthritis (OA). We found that miR-365 was up-regulated by cyclic loading and IL-1β stimulation in articular chondrocytes through a mechanism that involved the transcription factor NF-κB. miR-365 expressed significant higher level in rat anterior cruciate ligament (ACL) surgery induced OA cartilage as well as human OA cartilage from primary OA patients and traumatic OA Patients. Overexpression of miR-365 in chondrocytes increases gene expression of matrix degrading enzyme matrix metallopeptidase 13 (MMP13) and collagen type X (Col X). The increase in miR-365 expression in OA cartilage and in response to IL-1 may contribute to the abnormal gene expression pattern characteristic of OA. Inhibition of miR-365 down-regulated IL-1β induced MMP13 and Col X gene expression. We further showed histone deacetylase 4 (HDAC4) is a direct target of miR-365, which mediates mechanical stress and inflammation in OA pathogenesis. Thus, miR-365 is a critical regulator of mechanical stress and pro-inflammatory responses, which contributes cartilage catabolism. Manipulation of the expression of miR-365 in articular chondrocytes by miR-365 inhibitor may be a potent therapeutic target for the prevention and treatment of osteoarthritis.
Highlights
Osteoarthritis (OA) is a degenerative joint disease characterized by degradation of articular cartilage, thickening of subchondral bone, and formation of osteophytes
We aim to address the role of mechanical sensitive miR-365 in OA by using human articular chondrocytes, an animal model and osteoarthritis patients and traumatic osteoarthritis patients
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Summary
Osteoarthritis (OA) is a degenerative joint disease characterized by degradation of articular cartilage, thickening of subchondral bone, and formation of osteophytes. MiR-140 expression is significantly decreased in human OA chondrocytes [16], favoring an increased expression of its target genes and a role in cartilage degradation. MiR-146a was shown to be involved in human chondrocyte apoptosis in response to mechanical injury, and may contribute to the pathogenesis of OA [20]. These findings suggest that miRNAs play critical roles in skeletal development and diseases. We have identified that mechanical loading up-regulated miR-365 in growth plate chondrocytes. IL-1β significantly reduced expression of H8 DofA15C4 mRNA, which resembled the effect of miR-365 overexpressing chondrocytes (Figure 6B). miR-365 ovoseyrvenexereprgxrpiessrtesicsioseinfnfegacntcdohnoInLthd-e1roβdcoytwrteensa-trm(eFgiegunultartehioa6nvBeo).faHmsDyiRAn-e3Cr64g5i(sFotiivgceurerefexfe6pcBrte).soFsniuortnthheaenrdmdoowIrLen-,-1irnβehgtiurbelitaaittominoenonftomfhiHaRv-De36A5aC4 (Firgeudruec6eBd)t.hFeuIrLt-h1eβrminodruec,eidnhcaibtaitbioolnicoeffmfeciRt a-3s6s5horewdnubceydsitghneifIiLca-1nβt iinnhdibuictieodncoaftaMbMolPic13ef(fFeicgtuarses6hCo)w. n byTsaigknenifitcoagnetthinerh,itbhietisoenfionfdMingMs Psu1g3g(eFsitgtuhraet 6mCiR).-T3a65kednirteocgtleytthaerrg,etthseHseDfiAnCd4iningshusumgagnecsht othnadtromciyRte-3s65 diraencdtlymteadrgiaettessHitsDcAatCab4oilnicheuffmecatns. chondrocytes and mediates its catabolic effects
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