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.