Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment.

Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remain unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status - notably, obstructed fatty acid transportation - was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of BMP2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.

Fumarate Hydratase-Deficient Renal Cell Carcinoma With Predominant Tubulocystic Features Mimics Tubulocystic Renal Cell Carcinoma.

CONTEXT.­: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) rarely exhibits a predominant tubulocystic architecture with few other components. RCC with pure tubules and cysts lined by eosinophilic tumor cells with prominent nucleoli would raise the diagnosis of tubulocystic RCC. It is important to differentiate the 2 entities because they lead to different outcomes. OBJECTIVE.­: To address the concern, a multicenter study was implemented to explore useful clinicopathologic features in differentiation between tubulocystic FH-deficient RCC and tubulocystic RCC. DESIGN.­: Clinical factors included age, sex, tumor size, and outcome. Morphologic factors included cell morphology, presence or absence of a nontubulocystic component, and stromal findings. Immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing were performed to explore the protein expression and molecular profiles of the 2 entities. RESULTS.­: We evaluated 6 patients with tubulocystic RCC and 10 patients with tubulocystic FH-deficient RCC. Tubulocystic RCC exhibited a small size (<4.0 cm, pT1a), low Ki-67 index (<5%), retained FH, and negative 2SC expression. Tubulocystic FH-deficient RCC had a relatively large size and a high Ki-67 index. Perinucleolar haloes, loss of FH, and 2SC positivity were always observed. Pure tubulocystic architecture was not observed in FH-deficient RCC, because focal nontubulocystic components can always be seen. CONCLUSIONS.­: We emphasized multiple sectioning to identify a nontubulocystic architecture to exclude tubulocystic RCC. Moreover, tumor size, FH/2SC staining, and the Ki-67 index can differentiate tubulocystic FH-deficient RCC from tubulocystic RCC. The diagnosis of tubulocystic RCC was not recommended in renal mass biopsy because of the limited tissues sampled.

The effect of drug holiday on preventing medication-related osteonecrosis of the jaw in osteoporotic rat model.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with antiresorptive medications managing osteoporosis, such as bisphosphonates (BPs). To date, there is very limited evidence from prospective, controlled studies to support or refute the controversial prevention regimen that if a discontinuation of BPs before dentoalveolar surgery, so called "drug holiday", is effective in reducing the risk of MRONJ development in patients with osteoporosis. We proposed an experimental animal study, aiming to investigate the prevention of MRONJ following tooth extractions in osteoporotic condition, with the implementation of a BP drug holiday. Methods: Twenty rats were subjected to bilateral ovariectomy. After establishing the osteoporotic condition, all rats were exposed to weekly injections of zoledronate acid (ZA) for 8 weeks. After ZA treatment, 10 rats were subjected to dental extraction and defined as control group, and the rest 10 rats assigned to the DH group had a drug holiday of 8 weeks prior to dental extraction. Eight weeks after the dentoalveolar surgery, bone turnover biomarker in serum, occurrence of MRONJ-like lesion and histomorphometric assessment of osteonecrosis in mandible, and bone microarchitecture indices in femur, were examined. Results: Eight weeks after dental extraction, the DH group showed a recovered osteoclastic activity, indicated by significantly increased number of osteoclasts in the mandibles and serum level of C-terminal telopeptides of type I collagen, as compared to the control group. No significant differences were observed in the gross-view and histological occurrences of MRONJ-like lesions between the two groups.There was no significant difference in bone microarchitecture in the femur between the control and DH groups before ZA therapy and 8 weeks after dental extraction. Conclusion: Our data provided the first experimental evidence in the osteoporotic animal model that the implementation of a BP holiday in prior to dental extractions could partially recover osteoclastic activity, but could not alleviate the development of MRONJ-like lesion or exacerbate the osteoporotic condition in the femur. Longer-term drug holiday, or combination of drug holiday and other prophylaxes to prevent MRONJ in patients with osteoporosis could be worth exploring in future studies, to pave the way for clinical managements. The translational potential of this article: This in vivo prospective study reported that a recovery of osteoclastic activity by a BP drug holiday for 8 weeks in osteoporosis rats did not alleviate the development of MRONJ-like lesion followed by dental extractions. It contributes to the understanding of regimens to prevent MRONJ.

Injectable bioactive glass/sodium alginate hydrogel with immunomodulatory and angiogenic properties for enhanced tendon healing.

Tendon healing is a complex process involving inflammation, proliferation, and remodeling, eventually achieving a state of hypocellularity and hypovascularity. Currently, few treatments can satisfactorily restore the structure and function of native tendon. Bioactive glass (BG) has been shown to possess immunomodulatory and angiogenic properties. In this study, we investigated whether an injectable hydrogel fabricated of BG and sodium alginate (SA) could be applied to enhance tenogenesis following suture repair of injured tendon. We demonstrated that BG/SA hydrogel significantly accelerated tenogenesis without inducing heterotopic ossification based on histological analysis. The therapeutic effect could attribute to increased angiogenesis and M1 to M2 phenotypic switch of macrophages within 7 days post-surgery. Morphological characterization demonstrated that BG/SA hydrogel partially reverted the pathological changes of Achilles tendon, including increased length and cross-sectional area (CSA). Finally, biomechanical test showed that BG/SA hydrogel significantly improved ultimate load, failure stress, and tensile modulus of the repaired tendon. In conclusion, administration of an injectable BG/SA hydrogel can be a novel and promising therapeutic approach to augment Achilles tendon healing in conjunction with surgical intervention.

The clinicopathological features and prognosis of multifocal high-grade gliomas in adults with H3F3A mutation.

OBJECTIVES: To explore the clinicopathological features and prognosis of multifocal high-grade gliomas (M-HGGs) with H3F3A mutation in adults. METHODS: Four adult patients with H3F3A-mutant M-HGGs who were treated at our institution from August 2020 to December 2021 were reviewed, including clinical, pathological and radiologic data. A series of 16 adult patients with M-HGGs without H3F3A mutation was used as a comparative group. Progression-free survival (PFS) and overall survival (OS) were compared between the groups using the Kaplan-Meier method. RESULTS: All patients were IDH wild-type and TERT wild-type, and P53 was overexpressed. A patient with the H3 G34R mutation and 1 of 3 patients with the H3 K27 M mutation had MGMT promoter methylation. The lesions with the H3 G34R mutation were located in the cerebral hemisphere; the lesions with H3 K27 alterations were mainly in the midline structure, and the cerebral hemisphere could also be involved. One patient underwent subtotal resection (STR), and 3 patients underwent biopsy. All patients received radiotherapy, and the median PFS and OS were 9.5 months and 14.5 months, respectively. The clinical outcomes were similar to those of non-H3F3A-mutated M-HGGs patients (median PFS and OS were 7.0 months and 18.0 months, respectively). CONCLUSION: We describe the clinicopathological features and outcomes of 4 adult M-HGGs patients with H3F3A mutation, and found this mutation doesn't appear to have a negative outcome with the administration of current therapies.

Bioactive glass-elicited stem cell-derived extracellular vesicles regulate M2 macrophage polarization and angiogenesis to improve tendon regeneration and functional recovery.

Effective countermeasures for tendon injury remains unsatisfactory. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs)-based therapy via regulation of Mφ-mediated angiogenesis has emerged as a promising strategy for tissue regeneration. Still, approaches to tailor the functions of EVs to treat tendon injuries have been limited. We reported a novel strategy by applying MSC-EVs boosted with bioactive glasses (BG). BG-elicited EVs (EVB) showed up-regulation of medicinal miRNAs, including miR-199b-3p and miR-125a-5p, which play a pivotal role in M2 Mφ-mediated angiogenesis. EVB accelerated angiogenesis via the reprogrammed anti-inflammatory M2 Mφs compared with naïve MSC-EVs (EVN). In rodent Achilles tendon rupture model, EVB local administration activated anti-inflammatory responses via M2 polarization and led to a spatial correlation between M2 Mφs and newly formed blood vessels. Our results showed that EVB outperformed EVN in promoting tenogenesis and in reducing detrimental morphological changes without causing heterotopic ossification. Biomechanical test revealed that EVB significantly improved ultimate load, stiffness, and tensile modulus of the repaired tendon, along with a positive correlation between M2/M1 ratio and biomechanical properties. On the basis of the boosted nature to reprogram regenerative microenvironment, EVB holds considerable potential to be developed as a next-generation therapeutic modality for enhancing functional regeneration to achieve satisfying tendon regeneration.

Tumor-Targeting Polymer-Drug Conjugate for Liver Cancer Treatment In Vitro.

Bufalin (buf) has poor solubility in aqueous solution, poor tumor targeting, and many non-specific toxic and side effects. The advantages of high-molecular-weight polymer conjugates are that they can improve the water solubility of buf, prolong plasma half-life, and reduce non-specific toxicity. A novel water-soluble polymer-drug conjugate with buf and fluorescein pendants was prepared by the combination of reversible addition-fragmentation transfer (RAFT) polymerization and click chemistry. Its anticancer performance and cellular uptake behavior against liver cancer were investigated in vitro. The polymer-buf conjugates exhibit controlled release and tumor-targeting capabilities, showing promise for clinical applications.

Biosynthesized Bandages Carrying Magnesium Oxide Nanoparticles Induce Cortical Bone Formation by Modulating Endogenous Periosteal Cells.

Bone grafting is frequently conducted to treat bone defects caused by trauma and tumor removal, yet with significant medical and socioeconomic burdens. Space-occupying bone substitutes remain challenging in the control of osteointegration, and meanwhile activation of endogenous periosteal cells by using non-space-occupying implants to promote new bone formation becomes another therapeutic strategy. Here, we fabricated a magnesium-based artificial bandage with optimal micropatterns for activating periosteum-associated biomineralization. Collagen was self-assembled on the surface of magnesium oxide nanoparticles embedded electrospun fibrous membranes as a hierarchical bandage structure to facilitate the integration with periosteum in situ. After the implantation on the surface of cortical bone in vivo, magnesium ions were released to generate a pro-osteogenic immune microenvironment by activating the endogenous periosteal macrophages into M2 phenotype and, meanwhile, promote blood vessel formation and neurite outgrowth. In a cortical bone defect model, magnesium-based artificial bandage guided the surrounding newly formed bone tissue to cover the defected area. Taken together, our study suggests that the strategy of stimulating bone formation can be achieved with magnesium delivery to periosteum in situ and the proposed periosteal bandages act as a bioactive media for accelerating bone healing.

Mechanism of a Herbal Formula Associated with Prognosis and Immune Infiltration in LIHC: Transcriptomics Analysis and Molecular Dynamics Simulations.

Background: The aim of this study is to explore the interactions between effective monomers of herbal formulas and their therapeutic targets using systems biology approaches which may be a promising approach to unraveling their underlying mechanisms. Shentao Ruangan decoction (STRGD), which has been experimentally, clinically demonstrated to be effective in treating liver hepatocellular carcinoma (LIHC), was selected. Methods: Bioactive ingredients and drug targets of STRGD were retrieved from the traditional Chinese medicine systems pharmacology database and analysis platform and BATMAN-TCM databases. LIHC-related differentially expressed genes (DEGs) and key modules were identified by a weighted gene coexpression network analysis using The Cancer Genome Atlas data. The Kaplan-Meier analysis was used to investigate the relationship between STRGD tumor targets and patients survival. The CIBERSORT deconvolution algorithm was used to analyze the correlation between STRGD tumor targets and infiltrating immune cells. Enrichment analysis was used to analyze biological functions. Interactions between STRGD compounds and LIHC-immune-related genes were investigated using molecular docking and MDS. Results: We identified 24 STRGD tumor targets, which were found to be correlated with survival and the level of immune cell infiltration in LIHC patients. Immune infiltration, gene set enrichment, and Kyoto Encyclopedia of Genes and Genomes analyses highlighted the roles of T and B cell subsets, which were both related to activator protein 1 (AP1), in STRGD action. Docking studies and HPLC indicated that tanshinone IIA is the main compound of STRGD in LIHC treatment, and MDS showed that the potential LIHC-immune-related targets 1FOS and 1JUN firmly bind to tanshinone IIA. Conclusions: The mechanisms of STRGD in improving the immune and survival status of LIHC patients include interactions between STRGD compounds and LIHC-immune-related targets. The findings of this study can guide research studies on the potential usefulness of tanshinone IIA in the development of drugs targeting 1JUN and 1FOS for the treatment of LIHC.

Biodegradable magnesium implant enhances angiogenesis and alleviates medication-related osteonecrosis of the jaw in rats.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication associated with antiresorptive and antiangiogenic medications, of which impaired angiogenesis is a key pathological alteration. Since Magnesium (Mg)-based implants possess proangiogenic effects, we hypothesized that the biodegradable Mg implant could alleviate the development of MRONJ via enhancing angiogenesis. Methods: MRONJ model was established and divided into the Veh â€‹+ â€‹Ti group (Vehicle-treated rat, with Titanium (Ti) implant), BP â€‹+ â€‹Ti group (Bisphosphonate (BP)-treated rat, with Ti implant), BP â€‹+ â€‹Mg group (BP-treated rat, with Mg implant), BP â€‹+ â€‹Mg â€‹+ â€‹SU5416 group (BP-treated rat, with Mg implant and vascular endothelial growth factor (VEGF) receptor-2 inhibitor), BP â€‹+ â€‹Mg â€‹+ â€‹BIBN group (BP-treated rat, with Mg implant and calcitonin gene-related peptide (CGRP) receptor antagonist), and BP â€‹+ â€‹Mg â€‹+ â€‹SU5416+BIBN group (BP-treated rat, with Mg implant and VEGF receptor-2 inhibitor and CGRP receptor antagonist). The occurrence of MRONJ, alveolar bone necrosis, new bone formation and vessel formation were assessed by histomorphometry, immunohistochemistry, and micro-CT analysis. Results: Eight weeks after surgery, the BP â€‹+ â€‹Mg group had significantly reduced occurrence of MRONJ-like lesion and histological osteonecrosis, increased bone microstructural parameters, and increased expressions of VEGFA and CGRP, than the BP â€‹+ â€‹Ti group. By simultaneously blocking VEGF receptor-2 and CGRP receptor, the vessel volume and new bone formation in the BP â€‹+ â€‹Mg group were significantly decreased, meanwhile the occurrence of MRONJ-like lesion and histological bone necrosis were significantly increased. Conclusion: Biodegradable Mg implant could alleviate the development of MRONJ-like lesion, possibly via upregulating VEGF- and CGRP-mediated angiogenesis. Mg-based implants have the translational potential to be developed as a novel internal fixation device for patients with the risk of MRONJ. The Translational potential of this article: This work reports a biodegradable Mg implant which ameliorates the development of MRONJ-like lesions possibly due to its angiogenic property. Mg-based implants have the potential to be developed as a novel internal fixation device for patients at the risk of MRONJ.

Macrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis.

Epididymal white adipose tissue (eWAT) secretes an array of cytokines to regulate the metabolism of organs and tissues in high-fat diet (HFD)-induced obesity, but its effects on bone metabolism are not well understood. Here, we report that macrophages in eWAT are a main source of osteopontin, which selectively circulates to the bone marrow and promotes the degradation of the bone matrix by activating osteoclasts, as well as modulating bone marrow-derived macrophages (BMDMs) to engulf the lipid droplets released from adipocytes in the bone marrow of mice. However, the lactate accumulation induced by osteopontin regulation blocks both lipolysis and osteoclastogenesis in BMDMs by limiting the energy regeneration by ATP6V0d2 in lysosomes. Both surgical removal of eWAT and local injection of either clodronate liposomes (for depleting macrophages) or osteopontin-neutralizing antibody show comparable amelioration of HFD-induced bone loss in mice. These results provide an avenue for developing therapeutic strategies to mitigate obesity-related bone disorders.

Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/ß-catenin signaling.

Magnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key clinical manifestation, which currently lacks effective therapeutic options. Here we report that implantation of magnesium-containing implant stimulates bone formation and improves bone fracture healing in CFTR-mutant mice. Wnt/ß-catenin signaling in the bone is enhanced by the magnesium implant, and inhibition of Wnt/ß-catenin by iCRT14 blocks the magnesium implant to improve fracture healing in CFTR-mutant mice. We further demonstrate that magnesium ion enters osteocytes, increases intracellular cAMP level and activates ATF4, a key transcription factor known to regulate Wnt/ß-catenin signaling. In vivo knockdown of ATF4 abolishes the magnesium implant-activated ß-catenin in bones and reverses the improved-fracture healing in CFTR-mutant mice. In addition, oral supplementation of magnesium activates ATF4 and ß-catenin as well as enhances bone volume and density in CFTR-mutant mice. Together, these results show that magnesium implantation or supplementation may serve as a potential anabolic therapy for cystic fibrosis-related bone disease. Activation of ATF4-dependent Wnt/ß-catenin signaling in osteocytes is identified as a previously undefined mechanism underlying the beneficial effect of magnesium on bone formation.

Anterior Selective Lumbar Fusion Saving More Distal Fusion Segments Compared with Posterior Approach in the Treatment of Adolescent Idiopathic Scoliosis with Lenke Type 5: A Cohort Study with More Than 8-Year Follow-up.

OBJECTIVE: To investigate whether anterior selective fusion (ASF) could save more distal fusion segments compared with posterior approach in the treatment of Lenke type 5 adolescent idiopathic scoliosis with long term follow-up. METHODS: A retrospective cohort study. From 2008 to 2011, 22 AIS girls with Lenke type 5 who underwent ASF or posterior selective fusion (PSF) with more than 8-year follow-up, were extracted from the database. 13 girls in the ASF group had an average age of 14.3 ± 1.3 years and Risser sign of 3.3 ± 1.1; 9 PSF girls had an average age of 16.2 ± 3.6 years and Risser sign of 3.8 ± 1.5. The radiographic outcome was compared between groups preoperatively, 6-month postoperatively, 8-year postoperatively and at last follow-up (>8 years). RESULTS: The average follow-up duration was 8.7 ± 0.4 (ASF) and 8.8 ± 0.5 (PSF) years, respectively. There was no significant difference at baseline in age, Risser sign and preoperative curve pattern in the coronal and sagittal plane between the groups (P > 0.05). The ASF group had significantly shorter fusion segments (5.1 ± 0.6 vs. 7.0 ± 1.3) and decreased upper instrumented vertebra (UIV) (T11 ± 0.8 vs. T10 ± 0.8) than the PSF (P < 0.05); while no significant difference was found in the lower instrumented vertebra (LIV) and distal reserved segments (P > 0.05), which suggested that ASF could shorten the fusion segments by lowering UIV. The distal compensatory curve in the ASF group (9.0° ± 3.9°) was significantly larger than in the PSF group (3.3° ± 2.4°, P = 0.003), despite of no significant difference in the incidence of coronal imbalance (P > 0.05), indicating that both two approaches could obtain satisfactory correction in the coronal plane. In the sagittal plane, PSF patients had significantly larger lumbar lordosis (LL, 59.1° ± 10.5°), thoracic kyphosis (TK, 37.2° ± 13.3°) and proximal junctional angle (PJA, 13.3° ± 6.1°) at the last follow-up than the ASF (LL: 43.4° ± 9.4°; TK: 20.7° ± 8.4°; PJA: 4.7° ± 3.4°; P < 0.05), but without significant difference in proximal junctional kyphosis (PJK) and sagittal vertical axis (SVA) (P > 0.05). After controlling for age, Risser sign, and radiographic parameters related to the primary curve pattern, shorter fusion segments and more distal reserved segments still remained significant in the ASF group with greater Risser sign (P < 0.05). No major intra- or post-operative complications occurred. CONCLUSIONS: Both ASF and PSF could obtain satisfactory coronal and sagittal correction for Lenke 5 AIS; compared with PSF, ASF could shorten the fusion segments by lowering UIV, and save more distal fusion segments only in patients with greater skeletal maturity.

Natural History and Clinical Outcomes of Paravertebral Arteriovenous Shunts.

BACKGROUND AND PURPOSE: Paravertebral arteriovenous shunts (PVAVSs) are rare. Whether the intradural venous system is involved in drainage may lead to differences in clinical characteristics through specific pathophysiological mechanisms. This study aims to comprehensively evaluate the natural history and clinical outcomes of PVAVSs with or without intradural drainage. METHODS: Sixty-four consecutive patients with PVAVSs from 2 institutes were retrospectively reviewed. Lesions were classified as type A (n=28) if the intradural veins were involved in drainage; otherwise, they were classified as type B (n=36). The clinical course from initial presentation to the last follow-up was analyzed. RESULTS: The patients with type A shunts were older at presentation (52.5 versus 35.5 years, P<0.0001) and more likely to have lower spinal segments affected than patients with type B PVAVSs (67.8% versus 13.9%, P=0.00006). After presentation, the deterioration rates related to gait and sphincter dysfunction were significantly higher in patients with type A than type B shunts (gait dysfunction: 71.8%/y versus 17.0%/y, P=0.0006; sphincter dysfunction: 63.7%/y versus 11.3%/y, P=0.0002). According to the angiogram at the end of the latest treatment, 79% of type A and 75% of type B PVAVSs were completely obliterated. If the lesions were partially obliterated, a significantly higher clinical deterioration rate was observed in patients with type A shunts than those with type B shunts (69.9%/y versus 3.2%/y, P=0.0253). CONCLUSIONS: Type A PVAVSs feature rapid progressive neurological deficits; therefore, early clinical intervention is necessary. For complex lesions that cannot be completely obliterated, surgical disconnection of all refluxed radicular veins is suggested.

Primary mucosa-associated lymphoid tissue lymphoma in the midbrain: A case report.

BACKGROUND: Primary non-dural central nervous system mucosa-associated lymphoid tissue (MALT) lymphoma is a rare indolent B-cell lymphoma, with only a few reported cases worldwide. CASE SUMMARY: A 33-year-old man presented with a 5-mo history of left blepharoptosis and a 4-mo history of right limb numbness and weakness. Magnetic resonance imaging showed a significantly enhanced mass in the left midbrain. Subsequent positron emission tomography revealed that the lesion had increased glucose uptake. A stereotactic robotic biopsy supported a diagnosis of MALT lymphoma. Then he was treated with radiation therapy (30Gy/15F), which resulted in complete remission. We also review the literature on brain parenchymal-based MALT lymphoma, including the clinical presentation, treatment options, and outcomes. CONCLUSION: Although there is no consensus on the optimal treatment for this rare disease, patients can respond well when treated with radiotherapy alone.

Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis.

Critical size bone defects are frequently caused by accidental trauma, oncologic surgery, and infection. Distraction osteogenesis (DO) is a useful technique to promote the repair of critical size bone defects. However, DO is usually a lengthy treatment, therefore accompanied with increased risks of complications such as infections and delayed union. Here, we demonstrated that magnesium (Mg) nail implantation into the marrow cavity degraded gradually accompanied with about 4-fold increase of new bone formation and over 5-fold of new vessel formation as compared with DO alone group in the 5 mm femoral segmental defect rat model at 2 weeks after distraction. Mg nail upregulated the expression of calcitonin gene-related peptide (CGRP) in the new bone as compared with the DO alone group. We further revealed that blockade of the sensory nerve by overdose capsaicin blunted Mg nail enhanced critical size bone defect repair during the DO process. CGRP concentration-dependently promoted endothelial cell migration and tube formation. Meanwhile, CGRP promoted the phosphorylation of focal adhesion kinase (FAK) at Y397 site and elevated the expression of vascular endothelial growth factor A (VEGFA). Moreover, inhibitor/antagonist of CGRP receptor, FAK, and VEGF receptor blocked the Mg nail stimulated vessel and bone formation. We revealed, for the first time, a CGRP-FAK-VEGF signaling axis linking sensory nerve and endothelial cells, which may be the main mechanism underlying Mg-enhanced critical size bone defect repair when combined with DO, suggesting a great potential of Mg implants in reducing DO treatment time for clinical applications.

Stromal cell-derived factor-1 may play pivotal role in distraction-stimulated neovascularization of diabetic foot ulcer.

Diabetic foot ulcer (DFU) has become a major medical, social and economic concern worldwide. It is highly desirable to develop promising new solutions to effectively and appropriately treat DFU. In recent years, investigators have used an innovative technology called proximal tibial cortex transverse distraction (PTCTD) to treat DFU and have achieved satisfactory results in terms of improved wound healing and circumvention of amputation as a consequence of enhanced neovascularization and perfusion of the ulcerated feet after the operation, but the underlying mechanism has not been explored. Previous studies have suggested that in addition to stimulating osteogenesis, bone distraction also facilitates neovascularization, which may be associated with the chemokine stromal cell-derived factor-1 (SDF-1). As an important member of the chemokine family, SDF-1 is primarily responsible for the homing and migration of endothelial progenitor cells (EPCs) or bone marrow-derived mesenchymal stem cells (BMSCs), and plays a central role in the process of neovascularization. In vivo or in vitro experiments show that bone distraction can induce the expression of SDF-1 and increase its plasma concentration. Moreover, some researchers have found that an insufficient level of SDF-1 in the circulation and wounds of patients with DFU can lead to impaired neovascularization. Therefore, we believe that SDF-1 plays an important role in promoting neovascularization of DFU as a result of bone distraction. We summarize the currently relevant literature to put forward an undisclosed but meaningful mechanism of bone distraction in the treatment of DFU.

Further understanding on osteopetrotic femoral fractures: a case report and literature review.

BACKGROUND: Osteopetrosis is a genetic disease characterized by defects in osteoclast formation and function. There were a few cases of subtrochanteric femur fractures treated with dynamic hip screw (DHS) in patients with osteopetrosis, but unfortunately the healing outcome was rather poor. CASE PRESENTATION: We present our experience for treating a patient with intermediate autosomal recessive osteopetrosis (IRO) suffering from subtrochanteric femur fracture. In this case, we successfully used dynamic hip screw (DHS) internal fixation through meticulous preoperative planning and postoperative care, as well as application of surgical techniques. The patient displayed stable internal fixation with no limitation of activities during follow-up for 15 months. In addition to this case, a review of previous case reports showed an increasing number of case reports demonstrating that surgical treatment-related complications could be avoided preoperatively, intraoperatively, and postoperatively. CONCLUSION: DHS for this patient, who suffered from subtrochanteric fractures with osteopetrosis, was successfully implemented. In the light of a comprehensive literature review, preoperative planning, surgical techniques, and postoperative rehabilitation care can significantly reduce the complications.

The Effects of Calcitonin Gene-Related Peptide on Bone Homeostasis and Regeneration.

PURPOSE OF REVIEW: The goals of this review are two folds: (1) to describe the recent understandings on the roles of calcitonin gene-related peptide-α (CGRP) in bone homeostasis and the underlying mechanisms of related neuronal regulation and (2) to propose innovative CGRP-modulated approaches for enhancing bone regeneration in challenging bone disorders. RECENT FINDINGS: CGRP is predominantly produced by the densely distributed sensory neuronal fibers in bone, declining with age. Under mechanical and biochemical stimulations, CGRP releases and exerts either physiological or pathophysiological roles. CGRP at physiological level orchestrates the communications of bone cells with cells of other lineages, affecting not only osteogenesis, osteoclastogenesis, and adipogenesis but also angiogenesis, demonstrating with pronounced anabolic effect, thus is essential for maintaining bone homeostasis, with tuned nerve-vessel-bone network. In addition, its effects on immunity and cell recruitment are also crucial for bone fracture healing. Binding to the G protein-coupled receptor composited by calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1) on cellular surface, CGRP triggers various intracellular signaling cascades involving cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Peaking at early stage post-fracture, CGRP promotes bone formation, displaying with larger callus. Then CGRP gradually decreases over time, allowing normal or physiological bone remodeling. By elevating CGRP at early stage, low-intensity pulsed ultrasound (LIPUS), electrical stimulation, and magnesium-based bio-mineral products may promisingly accelerate bone regeneration experimentally in medical conditions like osteoporosis, osteoporotic fracture, and spine fusion. Excess CGRP expression is commonly observed in pathological conditions including cancer metastatic lesions in bone and fracture delayed- or non-healing, resulting in persistent chronic pain. To date, these discoveries have largely been limited to animal models. Clinical applications are highly desirable. Compelling evidence show the anabolic effects of CGRP on bone in animals. However, further validation on the role of CGRP and the underlying mechanisms in human skeletons is required. It remains unclear if it is type H vessel connecting neuronal CGRP to osteogenesis, and if there is only specific rather than all osteoprogenitors responsible to CGRP. Clear priority should be put to eliminate these knowledge gaps by integrating with high-resolution 3D imaging of transparent bulk bone and single-cell RNA-sequencing. Last but not the least, given that small molecule antagonists such as BIBN4096BS can block the beneficial effects of CGRP on bone, concerns on the potential side effects of humanized CGRP-neutralizing antibodies when systemically administrated to treat migraine in clinics are arising.

Papillary Renal Neoplasm With Reverse Polarity: A Clinicopathologic Study of 7 Cases.

Papillary renal neoplasm with reverse polarity is a form of recently described tumor. These tumors are defined by GATA3 positivity, negative vimentin staining, and the presence of both papillary structures and a layer of eosinophilic cells with apical nuclei and a granular cytoplasm. In the present report, we review 7 cases of papillary renal neoplasm with reverse polarity that were GATA3+ and vimentin-, consistent with past reports. In all 7 of these cases, we found that these tumors were additionally positive for 34ßE12. All 7 of these tumors were categorized as stage pT1. On histological examination, these tumors exhibited branching papillae with apical nuclei. All 7 of these patients were alive on most recent follow-up, with 6 being disease free and one having developed prostate cancer. Together, this overview of 7 additional cases of papillary renal neoplasm with reverse polarity offers further insight into this rare and poorly understood disease.