Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes

Abstract

Diabetes induces bone deterioration, which leads to increased risk of fracture, osteopenia, and osteoporosis. Thus, diabetes-associated bone fragility has been recognized as a diabetic complication. However, the pathophysiological effects of hyperglycemia on bone turnover remain unclear. Literature evidence demonstrates that anti-diabetic medications increase the risk of fractures in individuals with type 2 diabetes. Scopoletin is a naturally occurring hydroxycoumarin potentially exhibiting anti-inflammatory and antioxidant activities and ameliorating insulin resistance as an anti-diabetic agent. However, little is known regarding the effects of scopoletin on the impairment of bone remodeling that is caused by diabetes. The aim of this study was to identify that scopoletin was capable of inhibiting the impairment of bone remodeling and turnover in a mouse model of type 2 diabetes. Submicromolar scopoletin accelerated the formation TRAP-positive multinucleated osteoclasts (40.0 vs. 105.1%) and actin ring structures impaired by 33 mM glucose. Further, 1–20 μM scopoletin enhanced bone resorption and the induction of matrix-degrading enzymes in diabetic osteoclasts. The oral administration of 10 mg/kg scopoletin elevated serum RANKL/OPG ratio and osteocalcin level reduced in db/db mice along with an increase in BMD by ~6–14%; however, it was not effective in lowering blood glucose and hemoglobin glycation. In addition, the supplementation of scopoletin elevated the formation of trabecular bones and collagen fibers in femoral epiphysis and metaphysis with a thicker epiphyseal plate and cortical bones. Furthermore, 1–20 μM scopoletin enhanced ALP activity (4.39 vs. 7.02 nmol p-nitrophenyl phosphate/min/mg protein) and deposits of mineralized bone nodules in cultured osteoblasts reduced by 33 mM glucose. The treatment of diabetic osteoblasts with scopoletin stimulated the cellular induction of BMP-2 and osteopontin and Runx2 transcription. Accordingly, the administration of scopoletin protected mice from type 2 diabetes-associated bone loss through boosting bone remodeling via the robust induction of bone turnover markers of both osteoclasts and osteoblasts. These findings suggest that scopoletin could be a potential osteoprotective agent for the treatment of diabetes-associated bone loss and fractures.

Scopoletin inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells by regulating NF-κκB signaling pathway

“…6 In addition, its antioxidant activities have been indicated in multiple studies. 7,8 Scopoletin could inhibit the proliferation as well as motility of cervical cancer cells and promote the apoptosis of prostate cancer cells by regulating the PI3K/AKT signaling pathway. 8 Scopoletin also inhibits the proliferation of immature dendritic cells (DC) and has anti-angiogenic effects.…”

“…7,8 Scopoletin could inhibit the proliferation as well as motility of cervical cancer cells and promote the apoptosis of prostate cancer cells by regulating the PI3K/AKT signaling pathway. 8 Scopoletin also inhibits the proliferation of immature dendritic cells (DC) and has anti-angiogenic effects. In addition, scopoletin inhibits dendritic cell activation and the pathogenesis of autoimmune encephalomyelitis via nuclear factor kappa B (NF-κB) pathway.…”

Dietary Collagen Hydrolysates Retard Estrogen Deficiency-Induced Bone Loss through Blocking Osteoclastic Activation and Enhancing Osteoblastic Matrix Mineralization

“…This study investigated whether fsCH ameliorated the expression of osteogenic proteins of BMP-2, BSPII, and osteopontin during 21 day-osteoblastic differentiation. The cellular BMP-2 expression was enhanced significantly at the early–mid stage of differentiation [ 40 ]. The treatment of pre-osteoblastic cells with isoflavone, GPH, PH, and GP in osteogenic media did not influence the induction of BMP-2 ( Figure 6 D).…”

Scopoletin: a review of its pharmacology, pharmacokinetics, and toxicity

“…In vitro studies have revealed that scopoletin (1-20 µM) improves osteoclast formation in diabetes through RANKL and enhances osteoclast formation in diabetes by inducing BMP-2 and Runx2. Oral administration of 10 mg/kg scopoletin promotes the formation of bone trabeculae and collagen fibers in the femoral epiphysis and metaphysis of type 2 diabetes mice (Lee et al, 2021). Aldose reductase (AR) is a crucial ratelimiting enzyme that contributes to cataract induction among patients with diabetes.…”