Clinical characteristics, treatment and efficacy of calcaneal osteomyelitis: A systematic review with synthesis analysis 1118 reported cases.

BACKGROUND: Calcaneal osteomyelitis (CO) still poses great challenges to orthopaedic surgeons due to unique anatomic and functional features of the calcaneus. This study summarized the current data regarding clinical characteristics, treatment and efficacy of CO, based on an analysis of literature-reported cases. MATERIALS AND METHODS: We searched the PubMed, Embase, and Cochrane Library databases to find English and Chinese studies reporting on CO patients between 2000 and 2021, with available data for synthesis analysis. The quality of the included studies was evaluated by the National Institutes of Health (NIH) assessment scale. Effective data were extracted and pooled for analysis. RESULTS: Altogether 198 studies involving 1118 patients were included, with a male-to-female ratio of 2.3 (724 males and 310 females). The median age at CO diagnosis was 46 years, with a median symptom duration of 3 months. Injury-related infections (524 cases) and diabetic foot infections (336 cases) were the two most common causes, with ulcer (468 cases) and wound sinus or exudation (209 cases) being the predominant symptoms. The overall positive culture rate was 80.2%, with polymicrobial infections accounting for 18.1%. Staphylococcus aureus was the most frequently detected pathogen (42.7%), with fungal-related infections isolated in 17 cases. Although most patients received surgical interventions (96.9%), the recurrence rate was 20.1%. The incidence of infection relapse following partial calcanectomy, total calcanectomy, debridement with implantation of local antibiotics, and debridement with or without flap or skin coverage were 31.7%, 45.0%, 16.8%, and 15.1%, respectively. The overall incidence of limb amputation was 12.4%, with all-cause and CO-related mortalities of 2.8% and 0.2%, separately. CONCLUSIONS: CO shared similar characteristics with extremity chronic osteomyelitis, primarily affecting young males, with trauma and diabetic foot as the leading causes and Staphylococcus aureus as the most frequently detected pathogen. Despite surgery being the primary treatment modality, clinical outcomes remained unsatisfactory, marked by high rates of infection recurrence and limb amputation.

Effects of Staphylococcus aureus on stem cells and potential targeted treatment of inflammatory disorders.

Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered clearly. Meanwhile, with the intensive research on the mechanisms of stem cells in regulating various diseases, stem cell therapy is increasingly being attention because of its effectiveness and safety. As one of the most widely used stem cell in stem cell therapies, hematopoietic stem cell transplantation shows huge advantage in treatment of leukemia and other blood-malignant diseases. Besides, due to the effect of anti-inflammatory and immunomodulatory, mesenchymal stem cells could be a potential therapeutic strategy for variety infectious diseases. In this review, we summarized the effects of Staphylococcus aureus (S. aureus) and its components on different types of adult stem cells and their downstream signaling pathways. Also, we reviewed the roles of different kinds of stem cells in various disease models caused by S. aureus, providing new insights for applying stem cell therapy to treat infectious diseases.

Lipoteichoic acid restrains macrophage senescence via ß-catenin/FOXO1/REDD1 pathway in age-related osteoporosis.

Osteoporosis and its related fractures are common causes of morbidity and mortality in older adults, but its underlying molecular and cellular mechanisms remain largely unknown. In this study, we found that lipoteichoic acid (LTA) treatment could ameliorate age-related bone degeneration and attenuate intramedullary macrophage senescence. FOXO1 signaling, which was downregulated and deactivated in aging macrophages, played a key role in the process. Blocking FOXO1 signaling caused decreased REDD1 expression and increased phosphorylation level of mTOR, a major driver of aging, as well as aggravated bone loss and deteriorated macrophage senescence. Moreover, LTA elevated FOXO1 signaling through ß-catenin pathway while ß-catenin inhibition significantly suppressed FOXO1 signaling, promoted senescence-related protein expression, and accelerated bone degeneration and macrophage senescence. Our findings indicated that ß-catenin/FOXO1/REDD1 signaling plays a physiologically significant role that protecting macrophages from senescence during aging.

Bone-derived PDGF-BB drives brain vascular calcification in male mice.

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRß (p-PDGFRß) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRß/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.

Effects of Dopamine on stem cells and its potential roles in the treatment of inflammatory disorders: a narrative review.

Inflammation is the host's protective response against harmful external stimulation that helps tissue repair and remodeling. However, excessive inflammation seriously threatens the patient's life. Due to anti-inflammatory effects, corticosteroids, immunosuppressants, and monoclonal antibodies are used to treat various inflammatory diseases, but drug resistance, non-responsiveness, and severe side effect limit their development and application. Therefore, developing other alternative therapies has become essential in anti-inflammatory therapy. In recent years, the in-depth study of stem cells has made them a promising alternative drug for the treatment of inflammatory diseases, and the function of stem cells is regulated by a variety of signals, of which dopamine signaling is one of the main influencing factors. In this review, we review the effects of dopamine on various adult stem cells (neural stem cells, mesenchymal stromal cells, hematopoietic stem cells, and cancer stem cells) and their signaling pathways, as well as the application of some critical dopamine receptor agonists/antagonists. Besides, we also review the role of various adult stem cells in inflammatory diseases and discuss the potential anti-inflammation function of dopamine receptors, which provides a new therapeutic target for regenerative medicine in inflammatory diseases.

Elevated PDGF-BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRß Shedding from Pericytes.

Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain elusive. Here platelet-derived growth factor-BB (PDGF-BB) produced by preosteoclasts in bone is reported to promote age-associated hippocampal vascular impairment. Aberrantly elevated circulating PDGF-BB in aged mice and high-fat diet (HFD)-challenged mice correlates with capillary reduction, pericyte loss, and increased blood-brain barrier (BBB) permeability in their hippocampus. Preosteoclast-specific Pdgfb transgenic mice with markedly high plasma PDGF-BB concentration faithfully recapitulate the age-associated hippocampal BBB impairment and cognitive decline. Conversely, preosteoclast-specific Pdgfb knockout mice have attenuated hippocampal BBB impairment in aged mice or HFD-challenged mice. Persistent exposure of brain pericytes to high concentrations of PDGF-BB upregulates matrix metalloproteinase 14 (MMP14), which promotes ectodomain shedding of PDGF receptor ß (PDGFRß) from pericyte surface. MMP inhibitor treatment alleviates hippocampal pericyte loss and capillary reduction in the conditional Pdgfb transgenic mice and antagonizes BBB leakage in aged mice. The findings establish the role of bone-derived PDGF-BB in mediating hippocampal BBB disruption and identify the ligand-induced PDGFRß shedding as a feedback mechanism for age-associated PDGFRß downregulation and the consequent pericyte loss.

Serum Calcium Level Combined with Platelet Count May Be Useful Indicators for Assisted Diagnosis of Extremity Posttraumatic Osteomyelitis: A Comparative Analysis.

BACKGROUND: A previous study had reported that patients with osteomyelitis (OM) appeared to be more likely to develop hypocalcemia before and after surgery. Calcium sulfate (CS) is frequently used as a local antibiotic vehicle in the treatment of OM, which may also affect serum calcium level. However, whether changes of serum calcium level are caused by OM and/or local use of calcium sulfate remains unclear. Also, platelet (PLT) count plays a crucial predictive role in periprosthetic joint infections (PJIs), but its role in assisted diagnosis of OM is largely unknown. The purpose of this study was to determine whether serum calcium level and PLT count may be helpful in assisted diagnosis of PTOM. METHODS: Between January 2013 and December 2018, we analyzed 468 consecutive patients (392 males and 76 females), including 170 patients with posttraumatic OM (PTOM), 130 patients with aseptic bone nonunion (ABN), and 168 patients recovered from fractures with requirement of implant removal set as controls. Preoperative serological levels of calcium, phosphorus, and PLT were detected, and comparisons were conducted among the above three groups. Additionally, correlations and receiver operating characteristic (ROC) curves were displayed to test whether calcium level and PLT can differentiate patients with ABN and PTOM. RESULTS: Outcomes showed that the incidences of asymptomatic hypocalcemia (PTOM vs. ABN vs. controls = 22.94% vs. 6.92% vs. 8.82%, χ 2 = 21.098, P < 0.001) and thrombocytosis (PTOM vs. ABN vs. controls = 35.3% vs. 13.84% vs. 12.35%, χ 2 = 28.512, P < 0.001) were highest in PTOM patients. Besides, the mean serological levels of phosphorus in PTOM and ABN patients were significantly higher than those in the controls (P = 0.007). The Area Under the Curve (AUC) of the ROC curve outcomes revealed that, with the combination of serum calcium level with PLT count, the predictive role was acceptable (AUC 0.730, P < 0.001, 95% CI 0.681-0.780). Also, serological levels of calcium of 2.225 mmol/L and PLT count of 246.5 × 109/L were identified as the optimal cut-off values to distinguish patients with and without PTOM. However, age- and gender-related differences in serum calcium levels (age, P = 0.056; gender, P = 0.978) and PLT count (age, P = 0.363; gender, P = 0.799) were not found to be statistically significant in any groups. In addition, no significant correlations were identified between serum calcium level and PLT count (R = 0.010, P = 0.839). CONCLUSIONS: Asymptomatic hypocalcemia and thrombocytosis appeared to be more frequent in this cohort with PTOM. Serological levels of calcium and PLT count may be useful biomarkers in screening patients suspected of PTOM.

α-Hemolysin suppresses osteogenesis by inducing lipid rafts accumulation in bone marrow stromal cells.

α-hemolysin (Hla) is considered an essential virulent factor for Staphylococcus aureus (S. aureus) toxicity, the mechanism by which Hla affect bone metabolism is poorly understood. In this study, 2-month-old C57BL/6 mice were treated with Hla (40 µg/kg, i.p.) or S. aureus (1 × 106 CFU/ml, 100 µl, i.v.) with the presence or absence of methyl-ß-cyclodextrin (MßCD) (300 mg/kg, i.p.). MicroCT analysis showed progressive bone loss from week 2 to week 4 after Hla treatment, accompanied by a decreased osteoblasts and increased osteoclasts in femoral metaphysis in mice. Further, Hla stimulated the expression of Caveolin-1 in vivo and in vitro, activated lipid rafts accumulation in cell membrane of bone marrow stromal cells (BMSCs), and suppressed osteogenesis of BMSCs. Destruction of lipid rafts with MßCD or inhibition of Caveolin-1 with Daidzein blocked the detrimental effect of Hla on osteogenesis of BMSCs. Importantly, treating mice with MßCD rescued the loss of osteoblasts and increased osteoclastogenesis induced by Hla as well as the bone loss induced by S. aureus infection. Together, we demonstrate that Hla induces bone destruction directly by suppressing osteogenesis and indirectly by stimulating osteoclastogenesis, and that lipid rafts may mediate the detrimental effect of Hla and S. aureus on osteogenesis and bone formation.

Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development.

Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However, the mechanisms that initiate subchondral bone angiogenesis remain unclear. We show that abnormally increased platelet-derived growth factor-BB (PDGF-BB) secretion by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to osteoarthritis development. In mice after destabilization of the medial meniscus (DMM), aberrant joint subchondral bone angiogenesis developed during an early stage of osteoarthritis, before articular cartilage damage occurred. Mononuclear preosteoclasts in subchondral bone secrete excessive amounts of PDGF-BB, which activates platelet-derived growth factor receptor-ß (PDGFR-ß) signaling in pericytes for neo-vessel formation. Selective knockout of PDGF-BB in preosteoclasts attenuates subchondral bone angiogenesis and abrogates joint degeneration and subchondral innervation induced by DMM. Transgenic mice that express PDGF-BB in preosteoclasts recapitulate pathological subchondral bone angiogenesis and develop joint degeneration and subchondral innervation spontaneously. Our study provides the first evidence to our knowledge that PDGF-BB derived from preosteoclasts is a key driver of pathological subchondral bone angiogenesis during osteoarthritis development and offers a new avenue for developing early treatments for this disease.

The role of EGFR signaling in age-related osteoporosis in mouse cortical bone.

So far, there has been no effective cure for osteoporotic cortical bone, the most significant change in long bone structure during aging and the main cause of bone fragility fractures, because its underlying molecular and cellular mechanisms remain largely unknown. We used 3- and 15-mo-old mice as well as 15-mo-old mice treated with vehicle and gefitinib to evaluate structural, cellular, and molecular changes in cortical bone. We found that the senescence of osteoprogenitors was increased, whereas the expression of phosphorylated epidermal growth factor receptor (EGFR) on the endosteal surface of cortical bone down-regulated in middle-aged 15-mo-old mice compared with young 3-mo-old mice. Further decreasing EGFR signaling by gefitinib treatment in middle-aged mice resulted in promoted senescence of osteoprogenitors and accelerated cortical bone degeneration. Moreover, inhibiting EGFR signaling suppressed the expression of enhancer of zeste homolog 2 (Ezh2), the repressor of cell senescence-inducer genes, through ERK1/2 pathway, thereby promoting senescence in osteoprogenitors. Down-regulated EGFR signaling plays a physiologically significant role during aging by reducing Ezh2 expression, leading to the senescence of osteoprogenitors and the decline in bone formation on the endosteal surface of cortical bone.-Liu, G., Xie, Y., Su, J., Qin, H., Wu, H., Li, K., Yu, B., Zhang, X. The role of EGFR signaling in age-related osteoporosis in mouse cortical bone.

Is Hypercalcemia a Frequent Complication following Local Use of Calcium Sulfate with Antibiotics for the Treatment of Extremity Posttraumatic Osteomyelitis? A Preliminary Study.

BACKGROUND: Previous study had reported hypercalcemia as a frequent complication (20%) following local use of antibiotic-eluting calcium sulfate (CS) during treatment of periprosthetic joint infections (PJIs). However, whether this complication may occur in patients who receive local CS implantation for management of posttraumatic osteomyelitis (OM) remains unclear. METHODS: Between April 2016 and May 2017, we included 55 patients with extremity posttraumatic OM who received local antibiotic-loaded CS therapy. Serum calcium levels were detected preoperatively and on the 1st, 3rd, and 7th postoperative days (PODs). Comparisons were performed regarding serum calcium levels among the four time points and between two different CS volume groups (≤ 20 cc group and > 20 cc group). Additionally, potential associations were examined regarding CS volume and preoperative calcium level with postoperative calcium levels, respectively. RESULTS: Altogether 46 males and 9 females were included, with a median CS volume of 20 cc. Outcomes showed that prevalence of asymptomatic hypocalcemia was more frequent, with 16.4% before surgery and 60%, 53.8%, and 25% on the 1st, 3rd, and 7th PODs, respectively. Hypercalcemia was not found in any patients, at any time point. In addition, significant differences were identified regarding serum calcium levels among different time points, suggesting significantly decreased calcium levels on the 1st (P < 0.001) and 3rd PODs (P < 0.001) and back to near preoperative level on the 7th POD (P = 0.334). However, no statistical differences were observed regarding serum calcium levels between the two CS volume groups at any time points (P > 0.05). Moreover, no significant links were identified between CS volume and postoperative calcium levels (P > 0.05). Serum calcium levels on the 3rd (P = 0.019) and 7th PODs (P = 0.036) were significantly associated with the preoperative calcium level. CONCLUSIONS: In contrast to what had occurred in PJI patients, asymptomatic hypocalcemia appeared to be more frequent in this cohort with posttraumatic OM. Hypercalcemia may be an infrequent complication before and after local CS use for the treatment of extremity posttraumatic OM.