Experimental confirmation of osteoarthritis repair in vivo using epigenetic reprogramming with small molecules

Abstract

Background: Osteoarthritis (OA) is a progressive degenerative joint disease that significantly impairs mobility and quality of life, particularly in aging populations. Current therapeutic approaches primarily focus on symptom relief but fail to address the underlying mechanisms of cartilage degeneration. In recent years, epigenetic reprogramming has emerged as a promising strategy for cellular rejuvenation, offering new perspectives for regenerative medicine.

Objective: This study aimed to evaluate the effectiveness of small chemical molecules (SCM) in epigenetic reprogramming for the treatment of osteoarthritis (OA) in an aging organism.

Design: A preclinical study was conducted using female Rattus norvegicus albinus rats (age > 2 years, weight 250–270 g) with induced OA. The postmenopausal state was simulated via the estrogen receptor blocker clomiphene citrate. SCM were administered at concentrations previously established for in vitro epigenetic reprogramming. Histological and histochemical analyses of knee joint tissues were performed using hematoxylin and eosin, Van Gieson, and PAS staining. Cartilage degeneration was assessed using the modified Mankin scale. Statistical analysis included Student's t-test and correlation analysis.

Results: SCM administration resulted in a significant increase in tibial epiphyseal cartilage thickness and enhanced mucopolysaccharide synthesis, indicating metabolic activation of aging chondrocytes. Nuclear-cytoplasmic index changes in mitotically active cartilage regions suggested epigenetic rejuvenation, particularly in the superficial and intermediate zones. Notably, the response to SCM varied depending on estrogen receptor blockade. Rats with OA and induced menopause receiving SCM demonstrated the most pronounced cartilage regeneration, whereas untreated postmenopausal OA groups exhibited the most severe histological deterioration.

Conclusions: The study confirms the potential of SCM for epigenetic reprogramming in age-related OA, leading to cartilage regeneration and metabolic activation of chondrocytes without oncogenic risks. The findings highlight the need for further investigation into the interaction between estrogens and epigenetic rejuvenation, which may have implications for OA treatment in postmenopausal women.

Keywords: epigenetic reprogramming; chondrocyte rejuvenation; osteoarthritis; small chemical molecules (SCMs); cartilage regeneration