The ratio of alpha-calcitonin gene-related peptide to substance P is associated with the transition of bone metabolic states during aging and healing.

Alpha-calcitonin gene-related peptide (αCGRP) and substance P (SP) are functionally correlated sensory neuropeptides deeply involved in bone homeostasis. However, they are usually studied individually rather than as an organic whole. To figure out whether they are interdependent, we firstly recorded the real-time αCGRP and SP levels in aging bone and healing fracture, which revealed a moderate to high level of αCGRP coupled with a low αCGRP/SP ratio in an anabolic state, and a high level of αCGRP coupled with a high αCGRP/SP ratio in a catabolic state, suggesting the importance of αCGRP/SP ratio in driving aging and healing scenarios. During facture healing, increase in αCGRP/SP ratio by adding αCGRP led to better callus formation and faster callus remodeling, while simultaneous addition of αCGRP and SP resulted in hypertrophic callus and delayed remodeling. The characteristics in inflammation and osteoclast activation further confirmed the importance of high αCGRP/SP ratio during catabolic bone remodeling. In vitro assays using different mixtures of αCGRP-SP proved that the osteogenic potential of the mixtures depended mostly on αCGRP, while their effects on osteoclasts and neutrophils relied on both peptides. These results demonstrated that αCGRP and SP were spatiotemporally interdependent. The αCGRP/SP ratio may be more important than the dose of a single neuropeptide in managing age-related and trauma-related bone diseases.

Low-Intensity Pulsed Ultrasound Promotes Osteogenic Potential of iPSC-Derived MSCs but Fails to Simplify the iPSC-EB-MSC Differentiation Process.

Induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) are a promising cell source for bone tissue engineering. However, iMSCs have less osteogenic potential than BMSCs, and the classical iPSC-EB-iMSC process to derive iMSCs from iPSCs is too laborious as it involves multiple in vitro steps. Low-intensity pulsed ultrasound (LIPUS) is a safe therapeutic modality used to promote osteogenic differentiation of stem cells. Whether LIPUS can facilitate osteogenic differentiation of iMSCs and simplify the iPSC-EB-iMSC process is unknown. We stimulated iMSCs with LIPUS at different output intensities (20, 40, and 60 mW/cm2) and duty cycles (20, 50, and 80%). Results of ALP activity assay, osteogenic gene expression, and mineralization quantification demonstrated that LIPUS was able to promote osteogenic differentiation of iMSCs, and it worked best at the intensity of 40 mW/cm2 and the duty cycle of 50% (LIPUS40/50). The Wnt/ß-catenin signaling pathway was involved in LIPUS40/50-mediated osteogenesis. When cranial bone defects were implanted with iMSCs, LIPUS40/50 stimulation resulted in a significant higher new bone filling rate (72.63 ± 17.04)% than the non-stimulated ones (34.85 ± 4.53)%. Daily exposure to LIPUS40/50 may accelerate embryoid body (EB)-MSC transition, but it failed to drive iPSCs or EB cells to an osteogenic lineage directly. This study is the first to demonstrate the pro-osteogenic effect of LIPUS on iMSCs. Although LIPUS40/50 failed to simplify the classical iPSC-EB-MSC differentiation process, our preliminary results suggest that LIPUS with a more suitable parameter set may achieve the goal. LIPUS is a promising method to establish an efficient model for iPSC application.

[Rheumatoid leptomeningitis: a case report and literature review].

To report the clinical, radiological and neuropathological findings of a patient with rheumatoid meningitis. The patient was a 71-year-old Chinese man with a two-year history of rheumatoid arthritis and no other significant medical history, who presented to our hospital recurrent weakness of his left extremities, dysarthria and a continuous bilateral hand tremor. Cerebrospinal fluid (CSF) and serum examinations were normal apart from a mildly raised serum perinuclear antineutrophil cytoplasmic autoantibody (p-ANCA). Brain magnetic resonance imaging (MRI) showed leptomeningeal enhancement in both frontal and parietal lobes, in addition to several old white matter infarcts. Meningeal biopsy showed numerous infiltrating macrophages and lymphocytes within the leptomeninges. The patient responded clinically and radiologically to corticosteroid and cyclophosphamide therapy. The patient subsequently developed herpes zoster over his left chest as a complication of his immunosuppressive treatment. His cyclophosphamide was ceased and intravenous immunoglobulin (IVIG) therapy was commenced, with good clinical response to both the herpes zoster and meningitis. According to the result of the biopsy, aseptic meningitis was considered the MRI results and the patient's clinical history were given, and a diagnosis of rheumatoid meningitis was made. The patient was p-ANCA positive. Although there was no evidence for cerebral vasculitis on biopsy, it remains a possibility that the patient's recurrent minor cerebral infarcts visible on MRI were vasculitic in nature.