Hmga1‐overexpressing lentivirus protects against osteoporosis by activating the Wnt/β‐catenin pathway in the osteogenic differentiation of BMSCs

Abstract

Postmenopausal osteoporosis is associated with bone formation inhibition mediated by the impaired osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs). However, identifying and confirming the essential genes in the osteogenic differentiation of BMSCs and osteoporosis remain challenging. The study aimed at revealing the key gene that regulated osteogenic differentiation of BMSCs and led to osteoporosis, thus exploring its therapeutic effect in osteoporosis. In the present study, six essential genes related to the osteogenic differentiation of BMSCs and osteoporosis were identified, namely, fibrillin 2 (Fbn2), leucine‐rich repeat‐containing 17 (Lrrc17), heat shock protein b7 (Hspb7), high mobility group AT‐hook 1 (Hmga1), nexilin F‐actin‐binding protein (Nexn), and endothelial cell‐specific molecule 1 (Esm1). Furthermore, the in vivo and in vitro experiments showed that Hmga1 expression was increased during the osteogenic differentiation of rat BMSCs, while Hmga1 expression was decreased in the bone tissue of ovariectomized (OVX) rats. Moreover, the expression of osteogenic differentiation‐related genes, the activity of alkaline phosphatase (ALP), and the number of mineralized nodules were increased after Hmga1 overexpression, which was partially reversed by a Wnt signaling inhibitor (DKK1). In addition, after injecting Hmga1‐overexpressing lentivirus into the bone marrow cavity of OVX rats, the bone loss, and osteogenic differentiation inhibition of BMSCs in OVX rats were partially reversed, while osteoclast differentiation promotion of BMSCs in OVX rats was unaffected. Taken together, the present study confirms that Hmga1 prevents OVX‐induced bone loss by the Wnt signaling pathway and reveals that Hmga1 is a potential gene therapeutic target for postmenopausal osteoporosis.

Atoh1 overexpression promotes Guinea pig bone marrow mesenchymal stem cells to differentiate into neural stem cell

“…In this experiment, lentiviral vectors carrying target genes were chosen to transfer into BMSCs, taking into account the growth characteristics and survival time of BMSCs. The lentivirus showed the highest activity between 72 and 120 h after being introduced into BMSCs, aligning with the expected transfection properties of lentivirus [ 20 , 21 ]. Thus, our group decided to measure gene expression 72 h post-transfection.…”

Molecular and Cellular Mechanisms of Osteoporosis

“…In vivo and in vitro experiments showed that HMGA1 expression increases during osteogenesis of rat BMSCs and decreases during ovariectomy. Bone loss during ovariectomy in rats was compensated by the introduction of a lentivirus inserting HMGA1 into the bone marrow cavity; therefore, HMGA1 is considered a potential gene therapy target for the treatment of osteoporosis [182]. The clinical potential of the adeno-associated virus, an inhibitor of the WNT/β-catenin signaling pathway antagonists SHN3 and SOST, was demonstrated in terms of enhanced osteoblast function and bone formation [183].…”

Network pharmacology analysis and experimental validation to explore the mechanism of kaempferol in the treatment of osteoporosis

“…OPG (osteoprotegerin) is a natural antagonist of RANKL, which can bind to RANKL and prevent it from binding with RANKL, thus inhibiting bone resorption 6 . Activating the Wnt/β- catenin pathway can promote the proliferation and differentiation of osteoblasts and increase bone formation 7 , 8 . Estrogen can inhibit bone resorption by reducing the formation of osteoclasts and prolonging their life span, and can also promote the activity of osteoblasts 9 .…”