Ginsenoside Rg3 Alleviates Aluminum Chloride-Induced Bone Impairment in Rats by Activating the TGF-ß1/Smad Signaling Pathway.

Aluminum (Al)-induced bone formation and metabolism disorder through inhibition of the TGF-ß1/Smad signaling pathway is one of the important mechanisms of bone impairment. Ginsenoside Rg3 (Rg3), a specific biological effector molecule, can provide protection to bones. Previously, we demonstrated that Rg3 can reverse aluminum chloride (AlCl3)-induced oxidative stress and metabolic disorder of bones; however, whether the TGF-ß1/Smad signaling pathway is involved in it remains unclear. First, we found that Rg3 attenuated Al-induced bone impairment in vivo and in vitro by relieving structural damage to the femur, increasing MC3T3-E1 cell activity, differentiation, mineralization, inhibition of cell apoptosis, and upregulating the extracellular matrix (ECM) synthesis and the expression of TGF-ß1/Smad signaling pathway key factors. Subsequently, in the signal pathway intervention experiment, the protective effect of Rg3 on bone impairment induced by Al was weakened; these results indicate that activating the TGF-ß1/Smad signaling pathway is one of the mechanisms of Rg3-attenuated Al-induced bone impairment.

Native Collagen II Relieves Bone Impairment through Improving Inflammation and Oxidative Stress in Ageing db/db Mice.

Ageing-related bone impairment due to exposure to hyperglycemic environment is scarcely researched. The aim was to confirm the improvement effects of undenatured type II collagen (UC II) on bone impairment in ageing db/db mice, and the ageing model was established by normal feeding for 48-week-old. Then, the ageing db/db mice were randomly assigned to UC II intervention, the ageing model, and the chondroitin sulfate + glucosamine hydrochloride control groups. After 12 weeks of treatment, femoral microarchitecture and biomechanical parameters were observed, biomarkers including bone metabolism, inflammatory cytokines, and oxidative stress were measured, and the gastrocnemius function and expressions of interleukin (IL) 1ß, receptor activator of nuclear factor (NF)-κB ligand (RANKL), and tartrate-resistant acid phosphatase (TRAP) were analyzed. The results showed that the mice in the UC II intervention group showed significantly superior bone and gastrocnemius properties than those in the ageing model group, including bone mineral density (287.65 ± 72.77 vs. 186.97 ± 32.2 mg/cm3), gastrocnemius index (0.46 ± 0.07 vs. 0.18 ± 0.01%), muscle fiber diameter (0.0415 ± 0.005 vs. 0.0330 ± 0.002 mm), and cross-sectional area (0.0011 ± 0.00007 vs. 0.00038 ± 0.00004 mm2). The UC II intervention elevated bone mineralization and formation and decreased bone resorption, inflammatory cytokines, and the oxidative stress. In addition, lower protein expression of IL-1ß, RANKL, and TRAP in the UC II intervention group was observed. These findings suggested that UC II improved bones impaired by T2DM during ageing, and the likely mechanism was partly due to inhibition of inflammation and oxidative stress.

S1 Guidelines on Bone Impairment in Spinal Cord Injury.

During the acute and chronic phase of spinal cord injury (SCI) bone turnover and structure are affected. Bone mineral density of lower limbs is decreased up to 28%-50% below that of age-matched peers at 12-18 mo post injury. Coexisting secondary etiologies of osteoporosis may be present, and during ageing additional loss of bone occurs. All these compose a complex canvas of bone impairment after spinal cord injury and make the therapeutical approach challenging. The risk of fragility fractures is increased after the 2nd decade post SCI affecting the functionality and quality of life of individuals with SCI. Diagnostic flaws, lack of a ranking system to categorize the degree of bone impairment similar to the one of World Health Organization, and evidence-based clinical guidelines for management in SCI requires interdisciplinary cooperation and appropriate planning of future research and interventions. Spinal Cord Section of Hellenic Society of Physical Rehabilitation Medicine convened an expert panel working group on bone and spinal cord injury at the Pan-Hellenic Congress 2018 of PRM in Athens Greece, to establish an evidence-based position statement for bone loss in individuals with SCI of traumatic or non-traumatic etiology. This was reviewed by an International Task Force and used to create S1 Guidelines. This first version S1 guideline will work towards to provide help with prophylactic basic osteoporosis therapy diagnostic and therapeutic decisions in acute and chronic phase and rehabilitation countermeasures against osteoporosis related with spinal cord injury.

PINK1/Parkin-Mediated Mitophagy Plays a Protective Role in the Bone Impairment Caused by Aluminum Exposure.

The pollution of aluminum (Al) in agricultural production and its wide application in food processing greatly increase the chance of human and animal exposure. Al can accumulate in bone and cause bone diseases by inducing oxidative stress. Mitophagy can maintain normal cell function by degrading damaged mitochondria and scavenging reactive oxygen species. However, the role of mitophagy in the bone impairment caused by Al is unknown. In this study, we demonstrated that PTEN induced putative kinase 1 (PINK1)/ E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy was activated in the bone impairment caused by Al in vivo. Then, the Al-induced mitophagy in Parkin-deficient mice and MC3T3-E1 cells were decreased. Meanwhile, Parkin deficiency exacerbated the bone impairment, mitochondrial damage, and oxidative stress under Al exposure, both in vivo and in vitro. In general, the results reveal that Al exposure can activate PINK1/Parkin-mediated mitophagy, and the PINK1/Parkin-mediated mitophagy plays a protective role in the bone impairment caused by Al.

IGF-1R/ß-catenin signaling axis is implicated in streptozotocin exacerbating bone impairment in ovariectomized rats.

OBJECTIVE: The aim of this study was to investigate the role of the insulin-like growth factor-1 receptor (IGF-1R)/ß-catenin signaling axis in bone impairment induced by hyperglycemia in ovariectomized rats. METHODS: Rats were divided into four groups. The sham group received sham operation and a single intraperitoneal administration of vehicle. The ovariectomy (OVX) group was subjected to bilateral OVX and vehicle injection. The streptozotocin (STZ) group received sham operation and a single STZ injection to induce hyperglycemia. The OVX + STZ group received bilateral OVX and a single STZ injection. Dual-energy X-ray absorptiometry measurement, bone biomechanics test, micro-computed tomography scan, and hematoxylin-eosin staining were performed to evaluate bone alteration in this model. The expression of relevant signals including IGF-1R, glycogen synthase kinase-3ß (GSK-3ß), and ß-catenin were examined by quantitative real-time polymerase chain reaction and western blot. RESULTS: The OVX, STZ, and OVX + STZ groups induced bone loss, attenuated bone strength, and impaired microarchitecture compared with the sham group, respectively. Compared with OVX, more serious bone damage was found in the OVX + STZ group, which showed enhanced phosphorylation of IGF-1R, GSK-3ß, and ß-catenin. CONCLUSION: OVX plus STZ induced more serious bone impairment than OVX alone, which involves the IGF-1R/ß-catenin signaling axis in the pathogenesis. This may provide a potential target for treatment of postmenopausal diabetic osteoporosis.

Bone impairment caused by AlCl3 is associated with activation of the JNK apoptotic pathway mediated by oxidative stress.

Exposure to aluminum (Al) inhibits bone formation, the principal mechanism possibly due to oxidative stress. However, little data is available that establishes the precise relationship. In this study, Wistar rats were exposed to 0 (GC), 0.4 (GL), 0.8 (GM) or 1.6 (GH) mg/L aluminum trichloride (AlCl3) in drinking water for 90 days, respectively. The concentrations of Al in serum and bone, serum markers of bone metabolism, bone mineral density (BMD) and body weight were measured. Histological changes within femurs were observed by H&E, ALP, and TRACP staining. Oxidative stress markers and JNK apoptotic pathway were detected in bone. The results indicate that AlCl3 exposure decreased BMD, numbers of ALP-positive osteoblasts and serum levels of bone formation markers (B-ALP, PICP and BGP), and caused damaged to the trabecular structure. Serum levels of bone resorption markers (TRACP-5b, CTX-I) and numbers of TRACP-positive osteoclasts increased in GL, but conversely, they decreased in GM and GH. In addition, AlCl3 caused oxidative stress, up-regulated expression of c-Jun and pro-apoptotic factors with increased p-JNK/JNK ratio and down-regulated expression of anti-apoptotic factor Bcl-2 in bone. Taken together, these results indicate that bone impairment caused by AlCl3 is associated with activation of the oxidative stress-mediated JNK apoptotic pathway.

Effect of glucocorticoid withdrawal on glucocorticoid inducing bone impairment.

Glucocorticoid (GC) withdrawal after a short-term use was common in clinical practice like immediate post-transplant period. However, previous studies without setting age-control group failed to determine whether the BMD recovery was sufficient and whether it is necessary to accept anti-osteoporosis therapy after GC withdrawal. The aim of this study was to investigate the effect of GC withdrawal on bone impairment in glucocorticoid-induced osteoporosis (GIOP) rats. Twenty-four female Sprague-Dawley rats (3 months' old) were randomly divided into two treatment groups: an untreated age-control group (Con, n = 12); another group receiving a dexamethasone injection (DEXA, n = 12). Animals in the Con group were euthanized at 3rd month (M3) and 6th month (M6), respectively. Six rats in the DEXA group were euthanized at 3rd month (M3), whereas GC intervention was withdrew in the remaining animals of DEXA group, which were euthanized at the end of 6th month (M6). Bone mass, bone microarchitecture, biomechanical properties of vertebrae, morphology, serum levels of PINP and ß-CTX were evaluated. Compared with the Con(M3) group, the Con(M6) group showed significantly better bone quantity, morphology and quality. Compared with the Con(M3) group, the DEXA (M3) group showed significantly lower BMC, BMD, BS/TV, BV/TV, Tb.N, Tb.Th, vBMD, bone strength, compressive displacement, energy absorption capacity, PINP levels, ß-CTX levels, and damaged trabecular morphology. And the same change trend was observed in the comparison between the Con(M6) group and DEXA (M6) group. Compared with the DEXA (M3) group, the DEXA (M6) group showed significantly higher BMC, BMD and AREA, but no significant difference in BS/TV, BV/TV, SMI, Tb.N, Tb.Th, Tb.Sp, vBMD, bone strength, bone stiffness, compressive displacement, energy absorption capacity, PINP levels, ß-CTX levels, and improvement in trabecular morphology was observed. These results indicate that the reverse effect of GC withdrawal for 3 months on bone impairment in GIOP rats was insufficient, which implied that related anti-osteoporosis treatment might be still necessitated after GC withdrawal in clinical setting.