Previous studies have reported that adenosine mono-phosphate-activated protein kinase (AMPK) activation can enhance osteoblast differentiation and mineralization; however, the underlying mechanism is not fully understood. Autophagy also serves an important role in osteoblast mineralization and bone homeostasis. The present study aimed to explore whether activation of AMPK could enhance osteoblast differentiation and mineralization via the induction of autophagy. The fracture healing and nonunion animal models were established and verified by X-ray imaging. Bone maturation was measured by Masson staining and the expression of AMPK, p-AMPK, microtubule-associated proteins 1A/1B light chain 3B II, and p62 in the fracture ends were detected by immunohistochemical staining. The mRNA expression levels of alkaline phosphatase (ALP), osteocalcin, runt-related transcription factor 2 and BCN1 were determined by reverse transcription-quantitative polymerase chain reaction. 5-Bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium staining was used to determine ALP activity and alizarin red staining was adopted to examine mineralization. Western blot analysis was performed to detect protein expression. Autophagosome was observed by Transmission electron microscopy. Small interfering (si)RNA was used to knock down the expression of target gene. In vivo experiments demonstrated that new bone mineralization and maturation was markedly restrained in the nonunion group, alongside decreased AMPK activation and autophagic activity, compared with in the fracture healing group. The results of an in vitro study indicated that AMPK activation stimulated the osteogenic differentiation of MC3T3-E1 cells, with increases in ALP activity, mineralization, and the mRNA expression levels of ALP, osteocalcin and runt-related transcription factor 2. Furthermore, AMPK activation induced autophagy, as determined by upregulation of microtubule-associated proteins 1A/1B light chain 3B, increased autophagosome density and downregulation of p62. In addition, inhibition of autophagy reversed the effects of AMPK activation on osteoblast differentiation. These results suggested that AMPK activation may stimulate osteoblast differentiation and mineralization via the induction of autophagy, and provides evidence to suggest that enhancing AMPK activation and autophagic activity may be a potential novel approach to promote fracture healing.
Acquisition of drug-resistant phenotypes is often associated with chemotherapy in osteosarcoma. A number of studies have demonstrated a critical role for autophagy in osteosarcoma development, therapy and drug resistance. However, the molecular mechanisms underlying the autophagy-mediated chemotherapy resistance of osteosarcoma cells remain largely unknown. In the present study, we determined the autophagy and microRNA-140 (miR-140-5p, miRBase ID: MIMAT0000431) expression induced by chemotherapeutic drugs in osteosarcoma cells. Then we determined the promotory role of miR-140-5p to the chemotherapy-induced autophagy. Our results demonstrated that miR-140-5p expression was highly induced during chemotherapy of osteosarcoma cells, and this was accompanied by up-regulated autophagy. The increased miR-140-5p expression levels up-regulated anticancer drug-induced autophagy in osteosarcoma cells and ameliorated the anticancer drug-induced cell proliferation and viability decrease. Importantly, miR-140-5p regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (IP3k2). Therefore, the results of the present study demonstrated that miR-140-5p mediated drug-resistance in osteosarcoma cells by inducing autophagy. The present study provides evidence of miRNA regulation of autophagy through modulation of IP3 signalling. The present study recognized a novel mechanism of chemoresistance in osteosarcoma cancers.
Rationale:Skipped multifocal extensive spinal tuberculosis (TB) involving the whole spine is very rare. So far, only 3 cases have been reported.Patient concerns:We report a rare case of skipped multifocal extensive TB involving the whole spine of a 33-year-old Chinese male. The patient had been asymptomatic until his symptom was significantly aggravated, which caused him to have difficulty in walking and sleeping. The whole spinal computed tomography (CT) scan showed multifocal worm-eaten and osteolytic bony destruction spread over noncontiguous multilevel vertebral involvement in cervical, thoracic, lumbar, and sacral. In addition, the patient presented with low back pain, progressive fever, night sweats, and weight loss. An open biopsy was undergone indicating granulomatous inflammation after thorough radiographic examinations and laboratory investigations, which to our knowledge have been rarely reported by the published medical reference literature.Dignoses:It was initially diagnosed as lymphoma, multiple myeloma, or a metastatic disease by the radiologist. Final pathology confirmed it as an atypical form of spinal TB, which is extremely rare.Interventions:The patient with no progressive severe neurological symptoms, spinal deformity, or a huge abscess was put on a combination of anti-TB treatment and discharged in an improved state to continue medication for a total of 12 months.Outcomes:This article is a case report, no outcomes.Lessons:Multifocal extensive spinal TB involving the whole spine is rarely reported in the literature, which presents with atypical presentations and imaging features. It is noticeable that the possibility of TB is considered for any skip lesions involving the spine cautiously. Meanwhile, careful physical examination, trials of anti-TB treatment, and using the whole spine MRI routinely also play an important role in the diagnosis and treatment of this disease.
Intraspinal peripheral PNETs are rare spinal tumours. Although imaging characteristics are not specific, a focal circumscribed lesion in a young individual at the intramedullary, extramedullary intradural, or extradural spinal location that shows hypointense and hyperintense signal on T1- and T2-weighted images, respectively, requires PNET to be considered in the differentials.
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