Impairment of type H vessels by NOX2-mediated endothelial oxidative stress: critical mechanisms and therapeutic targets for bone fragility in streptozotocin-induced type 1 diabetic mice.

Rationale: Mechanisms underlying the compromised bone formation in type 1 diabetes mellitus (T1DM), which causes bone fragility and frequent fractures, remain poorly understood. Recent advances in organ-specific vascular endothelial cells (ECs) identify type H blood vessel injury in the bone, which actively direct osteogenesis, as a possible player. Methods: T1DM was induced in mice by streptozotocin (STZ) injection in two severity degrees. Bony endothelium, the coupling of angiogenesis and osteogenesis, and bone mass quality were evaluated. Insulin, antioxidants, and NADPH oxidase (NOX) inhibitors were administered to diabetic animals to investigate possible mechanisms and design therapeutic strategies. Results: T1DM in mice led to the holistic abnormality of the vascular system in the bone, especially type H vessels, resulting in the uncoupling of angiogenesis and osteogenesis and inhibition of bone formation. The severity of osteopathy was positively related to glycemic levels. These pathological changes were attenuated by early-started, but not late-started, insulin therapy. ECs in diabetic bones showed significantly higher levels of reactive oxygen species (ROS) and NOX 1 and 2. Impairments of bone vessels and bone mass were effectively ameliorated by treatment with anti-oxidants or NOX2 inhibitors, but not by a NOX1/4 inhibitor. GSK2795039 (GSK), a NOX2 inhibitor, significantly supplemented the insulin effect on the diabetic bone. Conclusions: Diabetic osteopathy could be a chronic microvascular complication of T1DM. The impairment of type H vessels by NOX2-mediated endothelial oxidative stress might be an important contributor that can serve as a therapeutic target for T1DM-induced osteopathy.

Local Treatment of Osteoporotic Sheep Vertebral Body With Calcium Sulfate for Decreasing the Potential Fracture Risk: Microstructural and Biomechanical Evaluations.

STUDY DESIGN: In this study, calcium sulfate (CS) was injected through pedicle into the osteoporotic vertebral body in vivo in sheep, and micro-computed tomography analysis, histologic observation, and biomechanical test were performed. OBJECTIVE: To investigate the improvement on microstructure and biomechanical performance of lumbar vertebrae augmented with CS in osteoporotic sheep. SUMMARY OF BACKGROUND DATA: The present treatments for osteoporosis relies on systemic medications intended to increase the bone mineral density (BMD). Although effective, these time-consuming medications provide little protection from fracture in the "early period" after initiation of therapy. In this regard, the strategy of local treatment is to target specific areas of the skeletal system that are prone to osteoporotic fractures. However, there is little or no research focused on local treatment of osteoporotic vertebrae with CS. METHODS: Eight female sheep were induced to osteoporosis with bilateral ovariectomy and methylprednisolone administration for 12 months. After successful establishment of an osteoporotic model, lumbar vertebrae (L1-L4) in every sheep were randomly divided into 2 groups: CS group and control group (2 vertebrae in each group in every sheep). CS was injected into the vertebral body transpedicularly in the CS group and no treatments were performed in the control group. Three months later, all sheep were killed and all L1-L4 vertebrae were harvested. Thereafter, microstructure and biomechanical performance of the cancellous bone of the vertebral body were assessed through micro-computed tomography analysis, histologic observation, and biomechanical test, respectively. RESULTS: After a 12-month induction with ovariectomy and methylprednisolone administration, the mean BMD of the sheep lumbar vertebrae significantly decreased (>25%) compared with the value before induction, which demonstrated successful establishment of osteoporosis. Three months after injection of CS, CS was completely degraded without any remains in bone tissue and the quality of bone tissue (amount and density of the bone tissue) in the CS group was significantly higher than that in the control group. The ultimate load, stiffness, and energy absorption in the CS group were all significantly higher than those in the control group. CONCLUSIONS: The preliminary data suggest that local injection of CS can significantly improve the amount, density, and biomechanical performance of the bone trabeculae in osteoporotic vertebra. The local injection of CS could also be used as a new method to improve the physical microstructure and augment the mechanical properties in "high-risk" vertebral bodies, decreasing the potential fracture risk of patients with osteoporosis. The strict inclusion and exclusion criteria should be performed before treatment.

The Protective Effect of Cordymin, a Peptide Purified from the Medicinal Mushroom Cordyceps sinensis, on Diabetic Osteopenia in Alloxan-Induced Diabetic Rats.

The aim of this study was to investigate the protective effect of cordymin on diabetic osteopenia in alloxan-induced diabetic rats and the possible mechanisms involved. The diabetic rats received daily intraperitoneal injection with cordymin (20, 50, and 100 mg/kg/day) for 5 weeks. Cordymin could restore the circulating blood glucose, glycosylated hemoglobin (HbA1c), serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), and insulin levels in a dose-dependent manner. Also, the treatment of diabetic rats with cordymin could partially reverse the ß cells death and decrease the total antioxidant status (TAOS) in the diabetic rats. The results may directly and indirectly account for the possible mechanism of the beneficial effect of cordymin on diabetic osteopenia, which was confirmed with the increased bone mineral content (BMC) and bone mineral density (BMD) in diabetic rats (P < 0.05). All those findings indicate that cordymin may play a protective role in diabetic osteoporosis.

Anti-osteoporosis activity of Cibotium barometz extract on ovariectomy-induced bone loss in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Recent research has confirmed that Cibotium barometz could inhibits osteoclast formation with no affect on BMM cell viability. However, the influence of Cibotium barometz on osteoporosis in animals is relatively unknown. The purpose of this study is to systemically investigate the effects of Cibotium barometz extract (CBE) on ovariectomy-induced osteoporosis in rats. MATERIALS AND METHODS: A total of Seventy-two 3-month-old female Sprague-Dawley rats were used and randomly divided into sham-operated group and five ovariectomized (OVX) groups: OVX with vehicle; OVX with 17ß-estradiol (E2, 25 µg/kg/day); OVX with CBE of graded doses (100, 300, or 500 mg/kg/day). Daily oral administration of E2 or CBE began 4 weeks after the surgery and lasted for 16 weeks. Bone mass, bone turnover and strength were analyzed by DEXA, biochemical markers and three-point bending test. The trabecular bone microarchitecture was evaluated by MicroCT. RESULTS: CBE prevented total BMD decrease in the femur induced by OVX, which was accompanied by a significant decrease in skeletal remodeling, as was evidenced by the decreased levels of the bone turnover markers, such as osteocalcin (OC), alkaline phosphatese (ALP), deoxypyridinoline (DPD), and urinary Ca and P excretions. The treatment could also enhance the bone strength and prevent the deterioration of trabecular microarchitecture. CONCLUSIONS: The present study indicated that Cibotium barometz extract might be a potential alternative medicine for the prevention and treatment of postmenopausal osteoporosis.

Augmentation of pedicle screw stability with calcium sulfate cement in osteoporotic sheep: biomechanical and screw-bone interfacial evaluation.

STUDY DESIGN: Augmentation of pedicle screws with calcium sulfate cement (CSC) was performed in osteoporotic sheep. Biomechanical tests, micro-computed tomography (CT) analysis, and histological observation were performed. OBJECTIVE: To investigate the long-term biomechanical performance of pedicle screws augmented with CSC in vivo and evaluated the screw-bone interfacial bonding with micro-CT and histological techniques. SUMMARY OF BACKGROUND DATA: There is little information on the long-term biomechanical performance and screw-bone interfacial bonding of pedicle screws augmented with CSC in osteoporosis in vivo. METHODS: Twelve months after ovariectomy, bilateral pedicles of lumbar vertebrae (L1 to L5) of 6 female sheep were fixed with pedicle screws. One pedicle of each vertebral body was treated with a screw augmented with CSC (CSC group) and the contralateral pedicle was treated with a screw without any augmentation (control group). Three months later, the sheep were killed and biomechanical tests, micro-CT analysis, and histological observation were conducted on the isolated specimen vertebrae. RESULTS: Twelve months after ovariectomy, animal model of osteoporosis was established successfully. Both the axial and vertical stabilities of the pedicle screws in CSC group were significantly enhanced compared with those in the control group (P<0.05). Micro-CT reconstruction and analysis showed that there were more bone trabeculae around the screws in CSC group compared with those in control group (P<0.05), and the bone trabeculae were significantly denser than those in control group (P<0.05). Histological observation showed that CSC was completely degradated and bone trabeculae around the screws in CSC group were more and denser than that in the control group. Bone trabeculae held the screws tightly without any interspaces between screw and bone, which formed strong bonding between bone and screw. CONCLUSIONS: CSC can significantly improve screw-bone interfacial bonding and strengthen the long-term stability of pedicle screws in osteoporotic sheep. Augmentation with CSC may be a potentially useful method to increase the stability of pedicle screws in patients with osteoporosis.