miR4352b a cross-species modulator of SOSTDC1, targets dual pathway to regulate bone health and fracture healing

AUTHORS

Divya Rai, Anirban Sardar, Anuj Raj, Bhaskar Maji, Shikha Verma, Ashish Kumar Tripathi, Sanchita Gupta, Ashish Sharma, Yogeshwar Vikram Dhar, Ritu Trivedi

ABSTRACT

Mutations in SOST can lead to various monogenic bone diseases. Its paralog, SOSTDC1, shares 55 % protein sequence homology and belongs to the BMP antagonist class. Sostdc1−/− mice exhibit distinct effects on cortical and trabecular bone. Genetic polymorphisms in SOSTDC1 impacting peak bone mass makes SOSTDC1 gene, a candidate for influencing BMD variation in humans. SOSTDC1 is upregulated in bone loss conditions, altering BMP-responsive genes and signaling modulators, suggesting its dual BMP/Wnt antagonist role may enhance both pathways. Overexpression of SOSTDC1 confirmed its role as an osteogenic antagonist. Glycine max (Soy)-derived miR4352b, identified for cross-kingdom applications, precisely targets SOSTDC1, a key regulator of bone. SOSTDC1 competitively binds to BMP2 receptor, BMPR1A. Gma-miR4352b suppresses SOSTDC1 expression, enhancing osteogenesis and countering SOSTDC1's inhibition of osteogenic potential. Modeling estrogen deficiency to mimic elevated SOSTDC1 levels, we observed an inverse correlation with SOSTDC1 expression, while serum BMP2 and PINP levels increased following gma-miR4352b supplementation. In fracture healing, SOSTDC1's crucial role becomes evident in conditions of delayed fracture healing. As healing progresses, SOSTDC1 expression decreases. Gma-miR4352b, compared to scrambled miRNA, remarkably promotes callus formation, achieving 68 % healing by day 10, surpassing the scrambled group at 44 %. By the day 13, the treatment group exhibits advanced healing, challenging to find the callus, while the scrambled group maintains a healing rate similar to day10. The accelerated healing in the treatment group underscores the importance of SOSTDC1 in influencing early fracture healing, potentially through the activation of both BMP2 and Wnt signaling pathways.

The Regulation of Hyperglycaemia-Induced Exosomal Mir-6499-3p Derived from Vascular Endothelial Cell on Calcification/Senescence of Vascular Smooth Muscle Cells

AUTHORS

Jiayu Zhong, MingHao Yuan, Shuo Hu, En Zhou

ABSTRACT

Diabetes is a prevalent metabolic condition that is closely linked to aging, and its biggest associated risk is vascular related complications. The calcification and aging of blood vessels in diabetes play a significant role in the development of diabetic vascular complications. Growing evidence links exosomal microRNA to the process of diabetic vascular complications. The present study aims to explore the expression, regulatory mechanisms and functions of exosomal miR-6499-3p in the process of diabetic vascular complications. VSMCs could take up exosomes isolated from HUVEC(ECs-exosome) treated with high glucose(HG). These exosomes induced the calcification and senescence of VSMCs through a paracrine mechanism. We then found that HG elevated the expression level of miR-6499-3p both in HUVECs and ECs-exosome. Calcification and senescence of VSMCs can be promoted by ECs-exosomes following overexpression of miR-6499-3p. Furthermore, we demonstrated that the effects of exosomes on the calcification and senescence of VSMCs is mediated by Sclerosin-containing domain SOSTDC1, the potential target of the miR-6499-3p. Our data has shown that a specific role of exosomes from HG-treated HUVEC in regulating the calcification and senescence of VSMCs in a paracrine manner through the miR-6499-3p/SOSTDC1 pathway. Modulation of exosomal miR-6499-3p may provide a novel perspective on the treatment of diabetic vascular complications.