Abstract
Osteoporosis is a common metabolic bone disorder in the elderly population. The accumulation of bone microdamage is a critical factor of osteoporotic fracture. Neuropeptide Y (NPY) has been reported to regulated bone metabolism through Y1 receptor (Y1R). In this study the effects and mechanisms of Y1R antagonist on prevention for osteoporosis were characterized. In the clinical experiment, compared with osteoarthritis (OA), osteoporosis (OP) showed significant osteoporotic bone microstructure and accumulation of bone microdamage. NPY and Y1R immunoreactivity in bone were stronger in OP group, and were both correlated with bone volume fraction (BV/TV). In vivo experiment, Y1R antagonist significantly improved osteoporotic microstructure in the ovariectomized (OVX) rats. And Y1R antagonist promoted RUNX2, OPG and inhibit RANKL, MMP9 in bone marrow. In vitro cell culture experiment, NPY inhibited osteogenesis, elevated RANKL/OPG ratio and downregulated the expression of cAMP, p-PKAs and p-CREB in BMSCs, treated with Y1R antagonist or 8-Bromo-cAMP could inhibit the effects of NPY. Together, Y1R antagonist improved the bone microstructure and reduced bone microdamage in OVX rats. NPY-Y1R could inhibit osteoblast differentiation of BMSCs via cAMP/PKA/CREB pathway. Our findings highlight the regulation of NPY-Y1R in bone metabolism as a potential therapy strategy for the prevention of osteoporosis and osteoporotic fracture.
Highlights
Osteoporosis is one of the most common metabolic bone disorders in the elderly population
The results showed that Neuropeptide Y (NPY) inhibited the bone marrow stromal cells (BMSCs) osteogenesis through activation of Y1 receptor (Y1R), which might be involved with the cAMP/PKA/CREB pathway
In vitro, NPY inhibited osteogenesis and elevated RANKL/OPG ratio through Y1R via suppression of cAMP/PKA/CREB pathway in BMSCs. These results suggest that NPY inhibits the cAMP/PKA/CREB pathway in BMSCs through Y1R, and Y1R antagonist plays an anti-osteoporotic effect and promoted microdamage repair in ovariectomized rats
Summary
Osteoporosis is one of the most common metabolic bone disorders in the elderly population. Postmenopausal women with osteoporosis are at high risk for osteoporotic fracture, which result in pain, dysfunction, and even death. Due to the rapid growth in the incidence and economic burden of osteoporotic fracture, it is reasonable to focus on the prevention and treatment of postmenopausal osteoporosis (PMO). Osteoporosis is diagnosed clinically by the measurement of bone mineral density (BMD), while BMD alone is not sufficient to explain fracture incidence. Bone quality generally refers to the effects of skeletal factors that affect fracture but are not accounted for by bone mass or BMD [1]. Studies have revealed that there are several characteristics of bone which have been proposed as critical factors of bone quality, including bone microdamage [2,3,4]
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