Lithium prevents glucocorticoid-induced osteonecrosis of the femoral head by regulating autophagy.

Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms.

ß-catenin inhibition disrupts the homeostasis of osteogenic/adipogenic differentiation leading to the development of glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased ß-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting ß-catenin signaling in glucocorticoid-induced GONFH rats. Col2+ lineage largely contributes to BMSCs and was found an osteogenic commitment in the femoral head through 9 mo of lineage trace. Specific deletion of ß-catenin gene (Ctnnb1) in Col2+ cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that ß-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH and identify an ideal genetic-modified mouse model of GONFH.

Selenium nanoparticles/carboxymethyl chitosan/alginate antioxidant hydrogel for treating steroid-induced osteonecrosis of the femoral head.

Oxidative stress plays a crucial role in steroid-induced osteonecrosis of the femoral head (SONFH). Although several antioxidant strategies have been investigated for treating SONFH, their antioxidant efficiencies and therapeutic effects remain unsatisfactory. Here, we developed a selenium nanoparticles/carboxymethyl chitosan/alginate (SeNPs/CMC/Alg) antioxidant hydrogel and evaluated its ability to treat SONFH. In vitro assays indicated that the SeNPs/CMC/Alg hydrogel exhibited excellent properties, such as low cytotoxicity, sustained SeNPs release, and favorable antioxidant activity. Under oxidative stress, the SeNPs/CMC/Alg hydrogel promoted reactive oxygen species (ROS) elimination and enhanced the osteogenic and proangiogenic abilities of bone marrow mesenchymal stem cells (BMSCs). After establishing a rabbit model of SONFH, the SeNPs/CMC/Alg hydrogel was transplanted into the femoral head after core decompression (CD) surgery. Radiographic and histological analyses revealed that the hydrogel treatment alleviated SONFH by eliminating ROS and promoting osteogenesis and angiogenesis compared to those in the CD and CMC/Alg groups. In vitro and in vivo studies indicated that the Wnt/ß-catenin signaling pathway was activated by the SeNPs/CMC/Alg hydrogel in both hydrogen peroxide-conditioned BMSCs and necrotic femoral heads. These findings indicate that local transplantation of the SeNPs/CMC/Alg hydrogel is beneficial for treating SONFH, as it promotes ROS elimination and activation of the Wnt/ß-catenin signaling pathway.

Inflammatory Lesions of the Jaws.

This article defines the fascial and spatial anatomy of the suprahyoid neck region, delineates the role of CT and MR imaging, discusses the inflammatory conditions of the jaws and adjacent spaces and their clinical symptomatology, and illustrates the appearance of these conditions.

Obesity impairs revascularization and bone healing in a mouse model of osteonecrosis.

Osteonecrosis of the femoral head (ONFH) is a devastating bone disease that is caused by a disruption of blood supply leading to necrotic cell death. Clinically, it was found that obesity has a high prevalence with ONFH. However, it remains unclear how obesity may directly affect tissue regeneration and bone healing in osteonecrosis (ON). The purpose of this study is to investigate the effects of obesity and weight loss (WL) on ON healing. In this study, we induced obesity and WL in an established surgery-induced ON mouse model via feeding a high-fat diet (HFD) and altering the diet respectively. All mice received a surgical induction of ON of distal femoral epiphysis at the age of 12 weeks. HFD was switched to normal diet (ND) after ON surgery to induce WL. Mouse body weight was recorded weekly. Mouse body composition was scanned by DEXA (Dual-energy X-ray absorptiometry) right after sacrifice at the age of 16 weeks. The distal femoral bone samples were fixed and embedded for histology such as H&E, immunohistochemistry, and TRAP staining. In this study, we found that HFD-induced obesity impaired revascularization and bone remodeling showing decreased vessel areas and reduced osteoblast and osteoclast numbers. WL could rescue obesity-induced bone healing defects. Our study is the first to test the direct effects of obesity and WL on ON bone healing. We believe our work may provide new concepts for osteonecrosis treatment in obese patients.

Epiphyseal cartilage vascular architecture at the distal humeral osteochondritis dissecans predilection site in juvenile pigs.

Failure of endochondral ossification due to interruption of the vascular supply to the epiphyseal cartilage is a critical step in the development of osteochondritis dissecans (OCD). Herein we describe the vascular architecture of the distal humeral epiphyseal cartilage in pigs and identify characteristic features that have been associated with sites predisposed to OCD development across species. Distal humeral specimens were harvested from pigs (n = 5, ages = 1, 10, 18, 30, and, 42 days old) and imaged at 9.4T magnetic resonance imaging (MRI) using a 3D gradient recalled echo sequence. The MRI data were processed using a quantitative susceptibility mapping (QSM) pipeline to visualize the vascular architecture. Specimens were also evaluated histologically to identify the presence of ischemic epiphyseal cartilage necrosis (osteochondrosis [OC]-latens) and associated failure of endochondral ossification (OC-manifesta). The QSM data enabled visualization of two distinct vascular beds arising from the perichondrium at the lateral and medial aspects of the distal humeral epiphysis. Elongated vessels originating from these beds coursed axially to supply the lateral and medial thirds of epiphyseal cartilage. At 18 days of age and older, a shift from perichondrial to transosseous blood supply was noted axially, which appeared more pronounced on the lateral side. This shift coincided with histologic identification of OC-latens (30- and 42-day-old specimens) and OC-manifesta (18- and 42-day-old specimens) lesions in the corresponding regions. The vascular anatomy and its evolution at the distal humeral epiphysis closely resembles that previously reported at predilection sites of knee OCD, suggesting a shared pathophysiology between the knee and elbow joints.

[A Case of Anti-Resorptive Agents-Related Osteonecrosis of the Jaw and Extensive Loss of Maxillary Bone in a Patient of Breast Cancer].

A 74-year-old woman had a mastectomy for right breast cancer in 201X. Eight years later, the patient developed multiple bone metastases and was treated with denosumab by her previous doctor. A year after, she was diagnosed with anti-resorptive agents-related osteonecrosis of the jaw, and preservation treatment was performed. In 201X+11, the patient had difficulty walking and was admitted to our palliative care ward. A month later, her maxillary bone detached extensively and spontaneously. By applying infection preventive measures and in cooperation with the former doctor, dentist, and oral surgeon, as well as visiting the dental department in our hospital, the patient managed to continue eating what she liked. Jaw infection did not occur. The patient died of liver dysfunction due to liver metastasis 5 months following the extensive loss of the maxillary bone.

Radiologic findings of osteonecrosis, osteoradionecrosis, osteomyelitis and jaw metastatic disease with cone beam CT.

PURPOSE: The purpose of this study was to assess CBCT scans of patients with medication related osteonecrosis of the jaws (MRONJ), osteoradionecrosis (ORN), osteomyelitis (OM) and jaw metastatic disease (JM), evaluate the presence and extent of radiologic findings, identify radiologic parameters that may distinguish the four entities and last, introduce a new modified radiographic index (CRIm), in order to contribute to the diagnosis of these conditions. METHODS: Τwo major databases were retrospectively searched for fully documented and diagnosed CBCT scans of MRONJ, ORN, OM and JM from 2006 to 2019. 335 CBCT scans met the inclusion criteria and were assessed under standardized viewing conditions blindly by 2 observers. The CRIm index proposed in this study evaluates: lytic changes, sclerosis, periosteal bone formation, sequestration, non-healing extraction sockets and other findings which included: sinus implication, inferior alveolar canal implication and jaw fracture. Lytic changes, sclerosis, periosteal bone formation, sequestration and non-healing extraction sockets were scored as: absent (0), localized/single (1) and extensive/multiple (2). Each one of other findings were scored individually as: absent (0) and present (1). For statistical analysis t-test, Pearson's r correlation coefficient, one-way ANOVA and Bonferonni were performed. RESULTS: Extensive lytic changes were the most common finding, especially for ORN, where it occurred in all CBCT scans (100%). The mean value of the CRIm index differs significantly between CBCT scans with MRONJ and JM, as well as between those with OM and JM (Bonferroni p < 0.001). CONCLUSIONS: The new modified Composite Radiographic Index introduced in this study, appears to have improved an objective approach to the previously used Composite Radiographic Index by means of cumulative radiologic features. Τhe predominance of certain radiologic features in one or more of these entities may lead the diagnostician towards the correct diagnosis.

Osteonecrosis of the ear canal in a patient treated with bisphosphonate.

In this case report, a 68-year-old woman, with known insulin-dependent diabetes and myelomatosis, presented with ear pain in her right ear. Otomicroscopy showed exposed bone in the external auditory canal. The patient was examined with wound swab, biopsies, MRI and PET-CT scans to rule out necrotizing external otitis, cholesteatoma and malignancy. Later, the patient's bisphosphonate treatment for myelomatosis was suspected, because osteonecrosis of the external auditory canal is a rare side effect to this treatment. The bone lesion improved after local debridement and cessation of the bisphosphonate treatment.

Imaging of Müller-Weiss Disease.

Müller-Weiss disease (MWD) is the result of a dysplasia of the tarsal navicular bone. Over the adult years, the dysplastic bone leads to the development of an asymmetric talonavicular arthritis with the talar head shifting laterally and plantarly, thus driving the subtalar joint into varus. From a diagnostic point of view, the condition may be difficult to differentiate from an avascular necrosis or even a stress fracture of the navicular, but fragmentation is the result of a mechanical impairment rather than a biological dysfunction.Standardized weight-bearing radiographs (anteroposterior and lateral views) of both feet are usually enough to diagnose MWD. Other imaging modalities such as multi-detector computed tomography and magnetic resonance imaging in early cases for the differential diagnosis can add additional details on the amount of cartilage affected, bone stock, fragmentation, and associated soft tissue injuries. Failure to identify patients with paradoxical flatfeet varus may lead to an incorrect diagnosis and management. Conservative treatment with the use of rigid insoles is effective in most patients. A calcaneal osteotomy seems to be a satisfactory treatment for patients who fail to respond to conservative measures and a good alternative to the different types of peri-navicular fusions. Weight-bearing radiographs are also useful to identify postoperative changes.

Administration of necrostatin-1 ameliorates glucocorticoid-induced osteonecrosis of the femoral head in rats.

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) is a serious complication of glucocorticoid treatment and is characterized by dysfunctional bone reconstruction at necrotic sites. Our previous study confirmed the protective potential of necrostatin-1, a selective blocker of necroptosis, in glucocorticoid-induced osteoporosis. In this study, rat models of GC-induced ONFH were established to evaluate the effects of necrostatin-1 on osteonecrotic changes and repair processes. Osteonecrosis was verified by histopathological staining. An analysis of trabecular bone architecture was performed to evaluate osteogenesis in the osteonecrotic zone. Then, necroptotic signaling molecules such as RIP1 and RIP3 were examined by immunohistochemistry. Histopathological observations indicated that necrostatin-1 administration reduced the incidence of osteonecrosis and the osteogenic response in subchondral areas. Additionally, bone histomorphometry demonstrated that necrostatin-1 intervention could restore bone reconstruction in the necrotic zone. The protective mechanism of necrostatin-1 was related to the inhibition of RIP1 and RIP3. Necrostatin-1 administration alleviated GC-induced ONFH in rats by attenuating the formation of necrotic lesions, recovering the function of osteogenesis, and suppressing glucocorticoid-induced osteocytic necroptosis by inhibiting the expression of RIP1 and RIP3.

The Lnc-HOTAIR/miR122/PPARγ signaling mediated the occurrence and continuous development of alcohol-induced Osteonecrosis of the femoral head.

This study aimed to explore the mechanism of alcohol-induced Osteonecrosis of the femoral head (ONFH) through in vivo and in vitro experiments. In vitro, the Oil Red O staining showed that ethanol promoted extracellular adipogenesis in a dose-dependent manner. ALP staining and alizarin red staining showed that ethanol inhibited the formation of extracellular mineralization in a dose-dependent manner. The Oil Red O staining showed that miR122 mimics and Lnc-HOTAIR SiRNA rescued extracellular adipogenesis induced by ethanol in BMSCs. Besides, we found that the high expression of PPARγ in BMSCs recruited histone deacetylase 3 (HDAC3) and histone methyltransferase (SUV39H1), which reduced the histone acetylation level and increased the histone methylation level in the miR122 promoter region, respectively. In vivo, the levels of H3K9ac, H3K14ac, and H3K27ac of miR122 promoter region in the ethanol group were significantly decreased compared to the control group, respectively. The levels of H3K9me2 and H3K9me3 of miR122 promoter region in the ethanol group were significantly increased compared to the control group. Lnc-HOTAIR/miR-122/PPARγ signaling mediated the alcohol-induced ONFH in the rat model. Furthermore, the persistent decrease of miR122 expression mediated the continuous progress of alcohol-induced ONFH after stopping alcohol consumption.

Application of biomaterials in treating early osteonecrosis of the femoral head: Research progress and future perspectives.

Osteonecrosis of the femoral head (ONFH), a progressive pathological process of femoral head ischemia and osteocyte necrosis, is a refractory orthopedic disease caused by multiple etiologies and there is no complete cure at present. With the extension of ONFH duration, osteocyte apoptosis and trabecular bone loss can decrease the load-bearing capacity of the femoral head, which leads to the collapse of the articular cartilage and subchondral bone. Therefore, an urgent clinical need exists to develop effective treatment strategies of early-stage ONFH for maintaining the hip joint function and preventing femoral head collapse. In recent years, extensive attention has been paid to the application of diverse biomaterials in treating early ONFH for sustaining the normal morphology and function of the autologous femoral head, and slowing disease progression. Herein, we review the research progress of bone grafts, metallic materials, bioceramics, bioglasses and polymer materials for early ONFH treatment, and discuss the biological mechanisms of bone repair and regeneration in the femoral-head necrotic area. We propose suggestions for future research directions, from a special perspective of improving the local microenvironment in femoral head by facilitating vessel-associated osteoclasts (VAOs) generation and coupling of bone-specific angiogenesis and osteogenesis, as well as inhibiting bone-associated osteoclasts (BAOs) and BAO-mediated bone resorption. This review can provide ideas for the research, development, and clinical application of biomaterials for treating early ONFH. STATEMENT OF SIGNIFICANCE: We believe that at least three aspects of this manuscript make it interesting to readers of the Acta Biomaterialia. First, we briefly summarize the incidence, pathogenesis, risk factors, classification criteria and treatment of early osteonecrosis of the femoral head (ONFH). Second, we review the research progress in biomaterials for early ONFH treatment and the biological mechanisms of bone repair and regeneration in femoral-head necrotic area. Third, we propose future research progress on improving the local microenvironment in femoral head by facilitating vessel-associated osteoclasts generation and coupling of bone-specific angiogenesis and osteogenesis, as well as inhibiting bone-associated osteoclasts and bone resorption. We hope this review can provide ideas for the research, development, and clinical application of biomaterials for treating early ONFH.

Osteonecrosis of the Tarsal Navicular: Not Always Spontaneous!

BACKGROUND: Mueller-Weiss disease, a rare and complex foot condition, is defined as spontaneous and progressive navicular fragmentation leading to midfoot pain and deformity. However, its exact etiopathogenesis remains unclear. We report a case series of tarsal navicular osteonecrosis to describe the clinical and imaging characteristics and etiologic profile of the disease. METHODS: This retrospective study included five women diagnosed as having tarsal navicular osteonecrosis. The following data were extracted from medical records: age, comorbidities, alcohol and tobacco consumption, history of trauma, clinical presentation, imaging modalities performed, treatment protocol, and outcomes. RESULTS: Five women with a mean age of 51.4 years (range, 39-68 years) were enrolled in the study. Mechanical pain and deformity over the dorsum of the midfoot was the main clinical presentation. Rheumatoid arthritis, granulomatosis with polyangiitis, and spondyloarthritis were reported by three patients. Radiographs revealed bilateral distribution in one patient. Three patients underwent computed tomography. It showed a fragmentation of the navicular bone in two cases.Magnetic resonance imaging was performed in one patient showing flattening of the lateral aspect of the navicular bone with signal abnormalities. Talonaviculocuneiform arthrodesis was performed in all of the patients. CONCLUSIONS: Mueller-Weiss disease-like changes may occur in patients with an underlying inflammatory disease such as rheumatoid arthritis and spondyloarthritis.

Germline VWF/MPRIP and somatoplasm FGA variants synergically confer susceptibility to non-traumatic osteonecrosis of the femoral head.

Non-traumatic osteonecrosis of the femoral head (ONFH) relies on multiple pathogenic factors, including intravascular coagulation, osteoporosis and lipid metabolism disorders. Despite extensively explored from various aspects, genetic mechanism underlying non-traumatic ONFH has not been fully elucidated. We randomly collected blood and necrotic tissue samples from 32 patients with non-traumatic ONFH as well as blood samples from 30 healthy individuals for whole exome sequencing (WES). Germline mutation and somatic mutation were analyzed to identify new potential pathogenic genes responsible for non-traumatic ONFH. Three genes might correlate with non-traumatic ONFH: VWF, MPRIP (germline mutations) and FGA (somatic mutations). Germline or somatic mutations in VWF, MPRIP and FGA correlate with intravascular coagulation, thrombosis, and consequently, ischemic necrosis of the femoral head.

The efficiency of genetically modified mesenchymal stromal cells combined with a functionally graded scaffold for bone regeneration in corticosteroid-induced osteonecrosis of the femoral head in rabbits.

Core decompression (CD) with mesenchymal stromal cells (MSCs) is an effective therapy for early-stage osteonecrosis of the femoral head (ONFH). Preconditioning of MSCs, using inflammatory mediators, is widely used in immunology and various cell therapies. We developed a three-dimensional printed functionally graded scaffold (FGS), made of ß-TCP and PCL, for cell delivery at a specific location. The present study examined the efficacy of CD treatments with genetically modified (GM) MSCs over-expressing PDGF-BB (PDGF-MSCs) or GM MSCs co-over-expressing IL-4 and PDGF-BB and preconditioned for three days of exposure to lipopolysaccharide and tumor necrosis factor-alpha (IL-4-PDGF-pMSCs) using the FGS for treating steroid-induced ONFH in rabbits. We compared CD without cell-therapy, with IL-4-PDGF-pMSCs alone, and with FGS loaded with PDGF-MSCs or IL-4-PDGF-pMSCs. For the area inside the CD, the bone volume in the CD alone was higher than in both FGS groups. The IL-4-PDGF-pMSCs alone and FGS + PDGF-MSCs reduced the occurrence of empty lacunae and improved osteoclastogenesis. There was no significant difference in angiogenesis among the four groups. The combined effect of GM MSCs or pMSCs and the FGS was not superior to the effect of each alone. To establish an important adjunctive therapy for CD for early ONFH in the future, it is necessary and essential to develop an FGS that delivers biologics appropriately and provides structural and mechanical support.

Ex vivo study of detergent-assisted intraosseous bone wash treatment of osteonecrosis.

Avascular necrosis (AVN) involves ischemic cell death of the bone. AVN leaves an abundance of necrotic lipids and debris in the bone marrow, which instigates inflammatory bone repair. Consequently, the necrotic bone microenvironment stimulates excessive bone resorption, leading to joint deformities and osteoarthritis. Here, we performed a detergent-assisted bone wash using poloxamer 407 (P407) to clean the necrotic bone environment by removing lipids and necrotic debris. The new concept was tested using an established ex vivo AVN model of porcine cadaver humeral heads. The P407 wash was performed using P407 solution and followed with saline via two intraosseous needles. Visual inspection and image analyses of average pixel light intensity showed that the P407 wash produced a better-cleaned bone than the saline wash. Analyses of the collected bone wash solution showed a two-fold increase in triglycerides (101 vs. 53 mmol/head, p = 0.006) and a 10-fold increase in the dry weight of the removed debris (1.34 vs. 0.13 g/head, p = 0.02) with the P407 wash compared to saline. The histological evaluation showed significantly decreased Oil-Red-O (fats) staining in the P407-washed bone compared with the saline-washed bone. The in vitro assays of Alizarin red and qPCR showed the P407 wash neither altered the osteogenic behaviors of porcine bone marrow-derived mesenchymal cells (pBMMCs) nor raised inflammatory responses of porcine bone marrow-derived macrophages (pBMMs). In conclusion, detergent-assisted bone wash using P407 produced a better removal of nonsoluble debris from the bone marrow space than the saline wash without causing changes to osteogenesis or inflammatory reactions.

Comparison of maximum and mean standardized uptake values of jaw pathologies with bone SPECT/CT: an especial focus on medication-related osteonecrosis of the jaw.

OBJECTIVES: To investigate the comparison of maximum and mean standardized uptake values (SUVs) of jaw pathologies with bone Single-photon emission computed tomography/computed tomography (SPECT/CT), and a special focus on medication-related osteonecrosis of the jaw (MRONJ). METHODS: Eighty-nine patients with jaw pathologies (63 MRONJ, 13 chronic osteomyelitis, 11 osteoradionecrosis and 2 primary intraosseous carcinoma) underwent bone SPECT/CT scans acquisition at 4 h after intravenous injection of Tc-99m hydroxymethylene diphosphonate in this prospective study. The evaluation of mean and maximum SUVs of jaw pathologies were performed using Q. Metrix and Xeleris workstation and defined the data automatically. Statistical analyses were performed by Pearson's correlation coefficient for comparison of maximum and mean SUVs and Mann-Whitney U-test for SUVs of MRONJ. A P value lower than 0.05 was considered to indicate statistical significance. RESULTS: Maximum SUVs of MRONJ, chronic osteomyelitis, osteoradionecrosis and primary intraosseous carcinoma were 17.6 ± 8.4, 21.7 ± 7.1, 11.9 ± 4.8 and 26.6 ± 7.0, respectively. Mean SUVs of MRONJ, chronic osteomyelitis, osteoradionecrosis and primary intraosseous carcinoma were 10.1 ± 4.9, 11.9 ± 3.3, 7.0 ± 2.8 and 10.1 ± 4.5, respectively. The maximum SUV of jaw pathologies was significantly correlated with the mean SUV (Y = 0.494X + 1.228; R2 = 0.786; P < 0.001). Furthermore, maximum and mean SUVs of MRONJ had significant differences in underlying diseases, medication and staging. CONCLUSION: The maximum and mean SUVs with bone SPECT/CT can be an effective tool for the quantitative evaluation of jaw pathologies, especially MRONJ.