YC-1 alleviates bone loss in ovariectomized rats by inhibiting bone resorption and inducing extrinsic apoptosis in osteoclasts

Abstract

Osteoporosis is a major health problem in postmenopausal women and the elderly that leads to fractures associated with substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, and the risk of fragility fractures has not yet been eliminated. There remains an unmet need for a broader range of therapeutics. Previous studies have shown that YC-1 has important regulatory functions in the cardiovascular and nervous systems. Many of the YC-1 effector molecules in platelets, smooth muscle cells and neurons, such as cGMP and μ-calpain, also have important functions in osteoclasts. In this study, we explored the effects of YC-1 on bone remodeling and determined the potential of YC-1 as a treatment for postmenopausal osteoporosis. Micro-computed tomography of lumbar vertebrae showed that YC-1 significantly improved trabecular bone microarchitecture in ovariectomized rats compared with sham-operated rats. YC-1 also significantly reversed the increases in serum bone resorption and formation in these rats, as measured by enzyme immunoassays for serum CTX-1 and P1NP, respectively. Actin ring and pit formation assays and TRAP staining analysis showed that YC-1 inhibited osteoclast activity and survival. YC-1 induced extrinsic apoptosis in osteoclasts by activating caspase-3 and caspase-8. In osteoclasts, YC-1 stimulated μ-calpain activity and inhibited Src activity. Our findings provide proof-of-concept for YC-1 as a novel antiresorptive treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone.

Calcitonin Induces Bone Formation by Increasing Expression of Wnt10b in Osteoclasts in Ovariectomy-Induced Osteoporotic Rats

“…Consistent with previous studies, we found that calcitonin treatment not only decreased the levels of serum bone resorption markers (i.e., TRAP5b and CTX-1) in OVX rats ( Figure 2 ) ( 14 , 15 ) but also led to increased levels of bone formation markers (i.e., osteocalcin and P1NP) in OVX rats ( 11 , 15 ). Because Wnt10b has recently been identified as a clastokine able to increase osteoblast activity, the finding that increased Wnt10b serum levels are correlated with osteocalcin and Wnt10b expression in bone marrow in calcitonin-treated OVX rats ( Figure 3 ) implies that Wnt10b may be involved in the effects of osteoclasts coupling to osteoblasts.…”

Role of nitric oxide in orthodontic tooth movement (Review)

“…By contrast, evidence has revealed an inhibitory effect of NO on osteoclasts at low concentrations. NO has been reported to increase osteoclast and osteoclast precursor cell apoptosis (101,(130)(131)(132). A novel NO donor, nitrosyl-cobinamide (NO-Cbi), has been found to reduce the RANKL/OPG gene expression ratio or directly inhibit osteoclast differentiation in vitro and in vivo (133).…”

Therapeutic Applications and Mechanisms of YC-1: A Soluble Guanylate Cyclase Stimulator

“…Wang and his colleagues evidenced that YC-1 inhibited bone resorption and induced extrinsic apoptosis of osteoclasts to reduce bone loss, which implied that YC-1 has potential application for use as an antiresorptive drug in postmenopausal osteoporosis [102]. Besides, YC-1 and its derivatives also have been mentioned to improve hepatic fibrosis, which mechanisms may be caused by inhibiting liver neutrophil infiltration as well as decreasing in TNF-α signaling and macrophage aggregation [103,104].…”