New therapeutic target for modulation of autophagy in osteoarthritis

Autophagy is a normal intracellular mechanism for recycling unnecessary or dysfunctional cellular components and proteins, thus preserving energy and alleviating stress to promote cellular survival. Numerous recent studies have demonstrated the importance of autophagy in normal cartilage maintenance and implicated deregulation of autophagy in the pathogenesis of osteoarthritis (OA), which remains as the most common chronic joint disease and the leading cause of disability worldwide. Evidently, cartilage-specific deletion of autophagy protein Atg5 induced aging-associated OA (1), suggesting a crucial role of autophagy in normal cartilage homeostasis. Similarly, decreased autophagy activity is associated with OA progression, as key autophagy markers decreased significantly in late OA, followed by increased chondrocyte apoptosis (2). Consistently, several studies subsequently demonstrated that genetic ablation (3) or pharmacological inhibition (4) of mammalian target of rapamycin (mTOR), which is a key suppressor of autophagy, have protective effects against OA in mice. It is likely that mTOR signaling may also have other effects on OA that are independent of autophagy, but regardless, therapeutic approaches that help maintain or stimulate autophagy at the articular cartilage appear as a promising avenue in managing OA.

A recent study showed evidence that autophagy activity at the articular cartilage is modulated by microRNA(miR)-128a (5). In this new study, Lian and colleagues surgically induced knee OA in rat by anterior cruciate ligament transection (ACLT) and found significant downregulation of multiple autophagy markers during OA progression, including Atg12. Concomitantly, miR-128a, which they showed could directly target and suppress Atg12, was significantly upregulated in OA. Similar changes of ATG12 and miR-128a expressions were also found in cartilage specimens harvested from patients with end-stage knee OA. Importantly, they further demonstrated that intra-articular injection of miR-128a directly induced cartilage degradation, and conversely, lentivirus-delivered antisense oligonucleotide of miR-128a (miR-128a-AS) was able to alleviate ACLT-induced cartilage erosion. Atg12 is likely only one of the many gene targets by which miR-128a modulates OA progression, as one previous study identified miR-128 as the top upstream regulator of hypomethylated OA susceptibility genes (6). Nevertheless, these exciting new findings strongly hinted at the therapeutic potential of miR-128a-AS, or other similar molecules that could interfere with miR-128a to promote autophagy, in treating OA.

Interestingly, this new study by Lian et al. (5) also investigated the potential mechanisms by which miR-128a was upregulated in OA. To this end, they treated cultured primary chondrocytes with interleukin-1β (IL-1β) to mimic inflammation and found that IL-1β treatment led to upregulation of miR-128a and downregulation of Atg12, which were consistent with their in vivo model. Hypothesizing that miR-128a might be epigenetically regulated, they then tested and found IL-1β treatment also decreased both the methylation of histone H3K27 and expression of enhancer zeste homology 2 (Ezh2), which is the histone methyltransferase driving H3K27 methylation. Finally, they demonstrated that overexpression or knockdown of Ezh2 reciprocally regulated the expression of miR-128a. Based on these findings, they proposed a working model to explain OA progression. Joint inflammation and upregulation of IL-1β results in downregulation of Eah2 and H3K27 methylation, which in turn upregulates miR-128a expression. miR-128a then suppresses Atg12 expression and autophagy in articular cartilage, thus driving chondrocyte apoptosis and cartilage erosion. While this working model is logically sound based on their observations alone, it is somewhat inconsistent with other previous studies in the field. Normal expression of Ezh2 is indeed required for proper cartilage development and normal chondrocyte functions during bone growth (7,8). However, it has been previously shown that EZH2 expression was upregulated, rather than downregulated, in both articular chondrocytes and synovial fibroblast in patients with OA (9,10). Importantly, intra-articular injection of Ezh2 inhibitor delayed OA development in mice (9), suggesting suppression of Ezh2 expression has protective effect against OA. This protective effect of Ezh2 inhibitor on OA is in part attributable to modulation of Wnt/β-catenin signaling. One of the many known genomic targets of Ezh2 is Sfrp1 (9,10), which encodes for a soluble inhibitor of Wnt signaling. Because activation of Wnt/β-catenin signaling is implicated in OA progression, and several preclinical studies have already demonstrated that Wnt inhibitors could ameliorate OA progression (11-13), inhibition of Ezh2 may similarly improve OA by derepression of Sfrp1 and consequent downregulation of Wnt signaling. Taken together, it is conceivable that the downregulation of Ezh2 observed by Lian et al. (5) in IL-1β treated chondrocytes is specific to the model they used, and whether or not pharmacological modulation of Ezh2 may have bone fide effects on autophagy in OA remain to be elucidated.

Acknowledgments

Funding: This work was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Jun Lu (Department of Orthopaedics, Southeast University Affiliated Zhongda Hospital, Nanjing, China).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aoj.2018.10.06). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bouderlique T, Vuppalapati KK, Newton PT, et al. Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis. Ann Rheum Dis 2016;75:627-31. [Crossref] [PubMed]
2. Carames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum 2010;62:791-801. [Crossref] [PubMed]
3. Zhang Y, Vasheghani F, Li YH, et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann Rheum Dis 2015;74:1432-40. [Crossref] [PubMed]
4. Carames B, Hasegawa A, Taniguchi N, et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis 2012;71:575-81. [Crossref] [PubMed]
5. Lian WS, Ko JY, Wu RW, et al. MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12. Cell Death Dis 2018;9:919. [Crossref] [PubMed]
6. Jeffries MA, Donica M, Baker LW, et al. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage. Arthritis Rheumatol 2014;66:2804-15. [Crossref] [PubMed]
7. Lui JC, Garrison P, Nguyen Q, et al. EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy. Nat Commun 2016;7:13685. [Crossref] [PubMed]
8. Dudakovic A, Camilleri ET, Xu F, et al. Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2. J Biol Chem 2015;290:27604-17. [Crossref] [PubMed]
9. Chen L, Wu Y, Wu Y, et al. The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/beta-catenin pathway. Sci Rep 2016;6:29176. [Crossref] [PubMed]
10. Trenkmann M, Brock M, Gay RE, et al. Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis. Ann Rheum Dis 2011;70:1482-8. [Crossref] [PubMed]
11. Lietman C, Wu B, Lechner S, et al. Inhibition of Wnt/beta-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis. JCI Insight 2018;3: [Crossref] [PubMed]
12. Deshmukh V, Hu H, Barroga C, et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage 2018;26:18-27. [Crossref] [PubMed]
13. Onuora S. Osteoarthritis: Wnt inhibitor shows potential as a DMOAD. Nat Rev Rheumatol 2017;13:634. [Crossref] [PubMed]