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Potential Methods of Targeting Cellular Aging Hallmarks to Reverse Osteoarthritic Phenotype of Chondrocytes

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Osteoarthritis (OA) is the most common chronic and disabling joint disease worldwide, causing pain and impaired mobility. Currently, no effective disease-modifying drugs are available to treat this disorder. Although not all elderly individuals have osteoarthritis, aging is considered the primary risk factor for this disease. However, the mechanisms by which aging and osteoarthritis correlate are still not completely understood. In this review, we revisit the features of OA chondrocytes and compare them with the cellular hallmarks of aging, including genomic instability, telomere attrition, epigenetic alteration, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, and altered intercellular communication. It is concluded that OA chondrocytes share many similar alterations with cellular aging. Next, based on findings from studies on chondrocytes and other cell types, we propose methods that can potentially reverse the osteoarthritic phenotype of chondrocytes back to a healthier state. Lastly, we discuss the current challenges and future perspectives. Specifically, we need to identify the hub(s) that regulate(s) the most changes observed in OA and aged chondrocytes, which can subsequently assist in the development of the most efficient treatments. In addition, OA chondrocyte-targeting therapeutics may negatively influence other healthy tissues, thus warranting careful examination.

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease that causes pain, physical disability, and life quality impairment. The pathophysiology of OA remains largely unclear, and currently no FDA-approved disease-modifying OA drugs (DMOADs) are available. As has been acknowledged, aging is the primary independent risk factor for OA, but the mechanisms underlying such a connection are not fully understood. In this review, we first revisit the changes in OA chondrocytes from the perspective of cellular hallmarks of aging. It is concluded that OA chondrocytes share many alterations similar to cellular aging. Next, based on the findings from studies on other cell types and diseases, we propose methods that can potentially reverse osteoarthritic phenotype of chondrocytes back to a healthier state. Lastly, current challenges and future perspectives are summarized.

SUBMITTER: He Y

PROVIDER: S-EPMC9312132 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Our previous study suggested that growth arrest and DNA damage-inducible protein 45beta (GADD45beta) prolonged the survival of hypertrophic chondrocytes in the developing mouse embryo. This study was undertaken, therefore, to investigate whether GADD45beta plays a role in adult articular cartilage.Gene expression profiles of cartilage from patients with late-stage osteoarthritis (OA) were compared with those from patients with early OA and normal controls in 2 separate microarray analyses. Histologic features of cartilage were graded using the Mankin scale, and GADD45beta was localized by immunohistochemistry. Human chondrocytes were transduced with small interfering RNA (siRNA)-GADD45beta or GADD45beta-FLAG. GADD45beta and COL2A1 messenger RNA (mRNA) levels were analyzed by real-time reverse transcriptase-polymerase chain reaction, and promoter activities were analyzed by transient transfection. Cell death was detected by Hoechst 33342 staining of condensed chromatin.GADD45beta was expressed at higher levels in cartilage from normal donors and patients with early OA than in cartilage from patients with late-stage OA. All chondrocyte nuclei in normal cartilage immunostained for GADD45beta. In early OA cartilage, GADD45beta was distributed variably in chondrocyte clusters, in middle and deep zone cells, and in osteophytes. In contrast, COL2A1, other collagen genes, and factors associated with skeletal development were up-regulated in late OA, compared with early OA or normal cartilage. In overexpression and knockdown experiments, GADD45beta down-regulated COL2A1 mRNA and promoter activity. NF-kappaB overexpression increased GADD45beta promoter activity, and siRNA-GADD45beta decreased cell survival per se and enhanced tumor necrosis factor alpha-induced cell death in human articular chondrocytes.These observations suggest that GADD45beta might play an important role in regulating chondrocyte homeostasis by modulating collagen gene expression and promoting cell survival in normal adult cartilage and in early OA.

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Potential Methods of Targeting Cellular Aging Hallmarks to Reverse Osteoarthritic Phenotype of Chondrocytes

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