Desferoxamine protects against glucocorticoid-induced osteonecrosis of the femoral head via activating HIF-1α expression

Glucocorticoid-induced osteonecrosis of the femoral head (GIOFH) is one of the most common complications of glucocorticoid administration. By chelating Fe²⁺, desferoxamine (DFO) was reported to be able to activate the HIF-1α/VEGF pathway and promote angiogenesis. In the present study, we examined whether DFO administration could promote angiogenesis and bone repair in GIOFH. GIOFH was induced in rats by methylprednisolone in combination with lipopolysaccharide. Bone repair was assessed by histologic analysis and microcomputed tomography (micro-CT). Vascularization was assessed by Microfil perfusion and micro-CT analysis. Immunohistochemical staining was performed to analyze the expression of HIF-1α, VEGF, and CD31. Our in vivo study revealed that DFO increased HIF-1α/VEGF expression and promoted angiogenesis and osteogenesis in GIOFH. Moreover, our in vitro study revealed that DFO restored dexamethone-induced HIF-1α downregulation and angiogenesis inhibition. Besides, our in vitro study also demonstrated that DFO could protect bone marrow-derived stem cells from dexamethone-induced apoptosis and mitochondrial dysfunction by promoting mitophagy and mitochondrial fission. In summary, our data provided useful information for the development of novel therapeutics for management of GIOFH.     

Switching to Denosumab or Bisphosphonates After Completion of Teriparatide Treatment in Women With Severe Postmenopausal Osteoporosis

ObjectiveTo compare bone mineral density (BMD) changes after 12 months of treatment with denosumab or bisphosphonates in postmenopausal women with severe osteoporosis after stopping teriparatide therapy.MethodsWe retrospectively analyzed 140 postmenopausal women (mean age, 74.2 years) with severe osteoporosis who had been treated with teriparatide for 18 to 24 months at our outpatient clinic in a tertiary endocrine center between 2006 and 2015. After stopping teriparatide therapy, they continued treatment with a bisphosphonate (alendronate, risedronate, ibandronate, or zoledronic acid) or denosumab while receiving daily vitamin D and calcium. BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) was measured by dual energy x-ray absorptiometry when teriparatide therapy was discontinued (baseline) and after 12 months of further treatment. Multivariate linear regression models were used to identify the predictors of BMD gain.ResultsAfter stopping teriparatide therapy, 70 women continued treatment with bisphosphonates and 70 received denosumab. LS, but not TH or FN, BMD gain was significantly greater in the denosumab group than in the bisphosphonates group at 12 months. Multivariate analysis showed that BMD gain at the LS was negatively associated with bisphosphonate versus denosumab treatment and positively associated with baseline serum total procollagen type I N-terminal propeptide. BMD gains at the FN were predicted by higher baseline serum urate levels. BMD gains at the TH and FN were negatively associated with pretreatment BMD gains at the same site.ConclusionTwelve months after stopping teriparatide therapy, sequential denosumab treatment appeared to yield higher additional LS BMD gain on average compared with bisphosphonates treatment.     

Higher circulating levels of chemokines CXCL10, CCL20 and CCL22 in patients with ischemic heart disease

Recruitment of leukocytes is one of the earliest events in the pathogenesis of ischemic heart disease (IHD) and chemokines play an important role in the migration of these cells into the inflammation sites. The aim of this study was to evaluate the CXCL10, CCL20 and CCL22 levels and the single nucleotide polymorphisms (SNPs) rs4508917, rs6749704 and rs4359426 in chemokine genes in patients with IHD to clarify any association. A total of 300 patients with IHD as having acute myocardial infarction (AMI; n = 100), stable angina (SA; n = 100) or unstable angina (UA; n = 100) and 100 healthy subjects as a control group were enrolled to study. Serum samples from all participants were tested for the CXCL10, CCL20 and CCL22 levels by using ELISA. The SNPs were determined by polymerase chain reaction–restriction length polymorphism (PCR–RFLP) method. The mean serum concentrations of CXCL10, CCL20 and CCL22 in AMI patients (395.97 ± 21.20 Pg/mL, 108.38 ± 10.31 Pg/mL and 1852.58 ± 205.77 Pg/mL), SA patients (405.48 ± 27.36 Pg/mL, 90.20 ± 7.69 Pg/mL and 2322.04 ± 231.23 Pg/mL) and UA patients (396.69 ± 22.79 Pg/mL, 141.87 ± 18.10 Pg/mL and 2754.89 ± 211.70 Pg/mL) were significantly higher than in the healthy group (179.38 ± 8.85 Pg/mL, 51.92 ± 4.62 Pg/mL and 451.82 ± 23.76 Pg/mL, respectively; P < 0.001). Similarly, the serum levels of CXCL10, CCL20 and CCL22 in total IHD patients (399.38 ± 13.77 Pg/mL, 113.49 ± 7.48 Pg/mL and 2309.84 ± 126.39 Pg/mL, respectively) were also significantly higher as compared with healthy subjects (P < 0.001). The serum levels of CCL20 and CCL22 in UA patients were significantly higher than those in SA and AMI patients, respectively (P < 0.01 and P < 0.003, respectively). The serum levels of CXCL10 and CCL20 in diabetic patients were significantly higher in comparison to non-diabetic patients (P < 0.05 and P < 0.02, respectively). The serum levels of CCL22 in dyslipidemic- and obese patients were also significantly higher in comparison with non-dyslipidemic- and non-obese patients, correspondingly (P < 0.05 and P < 0.01, respectively). There were no significant differences between men and women or between patients who treated with statin, aspirin, β-blockers or angiotensin converting enzyme (ACE) inhibitors and patients without mentioned treatment regarding the levels of chemokines. The frequency of the GG genotype at SNP rs4508917 in CXCL10 gene was higher, whereas the frequency of the AA genotype at SNP rs4359426 in CCL22 gene was lower in total patients with IHD as compared with healthy subjects (P < 0.04 and P < 0.002, respectively). These results showed that the higher levels of CXCL10, CCL20 and CCL22 were associated with IHD. The serum levels of chemokines may influence by the certain traditional risk factors of IHD and some studied SNPs, but did not influence by treatment and gender of patients.     

Assisting components within a resistance reflex of the stick insect, Cuniculina impigra

ABSTRACT. Rapid relaxation (shortening) of the femoral chordotonal organ in Cuniculina impigra Redtenbacher induces a depolarization followed by hyperpolarization of the fast and slow extensor tibiae motor neurons (FETi and SETi). The initial depolarization is caused by acceleration-sensitive units of the chordotonal organ. The reverse sequence of responses is induced in flexor motor neurons. The common inhibitor neuron (CI) is depolarized by both lengthening (stretch) and relaxation of the chordotonal organ.
The initial depolarization of FETi and SETi and the initial hyperpolarization of flexor motor neurons produced by rapid relaxation of the chordotonal organ and the depolarization of CI produced by lengthening of the chordotonal organ all oppose the resistance reflex response. However, these assisting components are weak compared to the resisting ones.     

Bone grafts,bone substitutes and orthobiologics: The bridge between basic science and clinical advancements in fracture healing

The biology of fracture healing is better understood than ever before, with advancements such as the locking screw leading to more predictable and less eventful osseous healing. However, at times one’s intrinsic biological response, and even concurrent surgical stabilization, is inadequate. In hopes of facilitating osseous union, bone grafts, bone substitutes and orthobiologics are being relied on more than ever before. The osteoinductive, osteoconductive and osteogenic properties of these substrates have been elucidated in the basic science literature and validated in clinical orthopaedic practice. Furthermore, an industry built around these items is more successful and in demand than ever before. This review provides a comprehensive overview of the basic science, clinical utility and economics of bone grafts, bone substitutes and orthobiologics.     

The role of biomechanical forces and MALAT1/miR-329-5p/PRIP signalling on glucocorticoid-induced osteonecrosis of the femoral head

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common orthopaedic disease. GIONFH primarily manifests clinically as hip pain in the early stages, followed by the collapse of the femoral head, narrowing of the hip joint space and damage to the acetabulum, resulting in severely impaired mobility. However, the pathogenesis of GIONFH is not clearly understood. Recently, biomechanical forces and non-coding RNAs have been suggested to play important roles in the pathogenesis of GIONFH. This study aimed to evaluate the role of biomechanical forced and non-coding RNAs in GIONFH. We utilized an in vivo, rat model of GIONFH and used MRI, μCT, GIONFH-TST (tail suspension test), GIONFH-treadmill, haematoxylin and eosin staining, qRT-PCR and Western blot analysis to analyse the roles of biomechanical forces and non-coding RNAs in GIONFH. We used RAW264.7 cells and MC3T3E1 cells to verify the role of MALAT1/miR-329-5p/PRIP signalling using a dual luciferase reporter assay, qRT-PCR and Western blot analysis. The results demonstrated that MALAT1 and PRIP were up-regulated in the femoral head tissues of GIONFH rats, RAW264.7 cells, and MC3T3E1 cells exposed to dexamethasone (Dex). Knockdown of MALAT1 decreased PRIP expression in rats and cultured cells and rescued glucocorticoid-induced osteonecrosis of femoral head in rats. The dual luciferase reporter gene assay revealed a targeting relationship for MALAT1/miR-329-5p and miR-329-5p/PRIP in MC3T3E1 and RAW264.7 cells. In conclusion, MALAT1 played a vital role in the pathogenesis of GIONFH by binding to (‘sponging’) miR-329-5p to up-regulate PRIP. Also, biomechanical forces aggravated the pathogenesis of GIONFH through MALAT1/miR-329-5p/PRIP signalling.