Karanjin counteracts OVX-induced bone loss by dual regulating bone remodeling

Abstract

Background: Osteoporosis is a common skeletal disorder characterized by reduced bone mass and compromised bone microarchitecture. Although medicines have been developed for osteoporosis treatment, most of them focus either on inhibiting bone resorption or on promoting bone formation. Natural compounds have low toxicity, high efficacy, and poly-pharmacological actions, making them potential candidates for osteoporosis treatment.

Purpose: This study investigates the therapeutic effects of karanjin (Ka) on osteoporosis.

Study design and methods: We established ovariectomy (OVX)-induced osteoporosis mouse model to evaluate the effects of Ka on bone health. Micro-CT was performed to examine bone morphological parameters. Bone histological staining was conducted to characterize bone resorption and formation processes. TRAP, ALP, and ARS staining experiments were performed to confirm the effects of Ka on osteoclasts and osteoblasts in vitro. Real-time PCR and immunoblot assay were used to assess the expression of marker genes of osteoclastogenesis and osteogenesis. Finally, we identify the potential mechanisms of Ka using network pharmacology analysis, immunofluorescence, and Co-IP assays.

Results: Ka counteracted OVX-induced bone loss through dual regulating bone resorption and formation. In vitro experiments confirmed that Ka suppressed osteoclastogenesis and promoted osteogenesis. Using network pharmacology, we identified JAK2 and GSK3B were potential targets of Ka. In osteoclasts, Ka blocked JAK2 phosphorylation by disrupting CBL-mediated K63 ubiquitination. In osteoblasts, Ka promoted osteogenesis by stabilizing β-catenin and activating canonical Wnt signaling.

Conclusion: Ka counteracted OVX-induced bone loss by inhibiting osteoclastogenesis and promoting osteogenesis. Our findings provide evidence for Ka being a promising therapeutic agent for osteoporosis.

Keywords: GSK3B; JAK2; Karanjin; Osteoblast; Osteoclast; Osteoporosis.