Spontaneous resolution of asymptomatic alumina matrix composite ceramic liner dissociation: a case report.

BACKGROUND: Total hip arthroplasty(THA)is widely used to treat end-stage hip disorders. Ceramic-on-ceramic total hip prostheses are widely used because of their durability. Alumina matrix composite (AMC), known as the fourth-generation ceramics, reduces implant fracture and wear rate compared to their predecessors. However, ceramic acetabular liner dissociation is a complication that necessitates revision of the AMC prostheses. To date, only few cases of AMC liner dissociation have been reported and all of which have been treated with revision surgery. Therefore, the prognosis of non-operated AMC liner dissociation remains unknown so far. CASE PRESENTATION: A 57-year-old man with avascular necrosis of the femoral head was treated with THA, wherein a Pinnacle® (DePuy, J&J, Warsaw, IN) acetabular cup and AMC liner were implanted. Intraoperative examination confirmed proper seating of the liner, whereas the initial postoperative radiograph revealed liner dissociation. The patient refused surgical revision due to the absence of symptoms and was discharged and followed-up. The patient made an uneventful recovery, and radiographic follow-up at 6-month post-operation showed that the liner was re-seated to its right position. No clinical or radiographic anomaly was found at the 15-month of postoperative follow-up. CONCLUSIONS: Here, we report an unprecedented case of AMC ceramic liner dissociation with spontaneous resolution. This case shows that ceramic liner dissociation could be asymptomatic, and careful postoperative examination of the patient is important. Spontaneous resolution is possible, but the underlying mechanism and the eligible patient to benefit from it must be investigated. Before clarifying these questions, revision surgery should be the first-line treatment.

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.

Combination of magnesium ions and vitamin C alleviates synovitis and osteophyte formation in osteoarthritis of mice.

INTRODUCTION: We previously demonstrated that magnesium ions (Mg2+) was a novel therapeutic alternative for osteoarthritis (OA) through promoting the hypoxia inducible factor-1α (HIF-1α)-mediated cartilage matrix synthesis. However, oxidative stress can inhibit the expression of HIF-1α, amplify the inflammation that potentially impairs the therapeutic efficacy of Mg2+ in OA. Vitamin (VC), a potent antioxidant, may enhance the efficacy of Mg2+ in OA treatment. This study aims to investigate the efficacy of combination of Mg2+ and VC on alleviating joint destruction and pain in OA. MATERIAL AND METHODS: Anterior cruciate ligament transection with partial medial meniscectomy induced mice OA model were randomly received intra-articular injection of either saline, MgCl2 (0.5 mol/L), VC (3 mg/ml) or MgCl2 (0.5 mol/L) plus VC (3 mg/ml) at week 2 post-operation, twice weekly, for 2 weeks. Joint pain and pathological changes were assessed by gait analysis, histology, western blotting and micro-CT. RESULTS: Mg2+ and VC showed additive effects to significantly alleviate the joint destruction and pain. The efficacy of this combined therapy could sustain for 3 months after the last injection. We demonstrated that VC enhanced the promotive effect of Mg2+ on HIF-1α expression in cartilage. Additionally, combination of Mg2+ and VC markedly promoted the M2 polarization of macrophages in synovium. Furthermore, combination of Mg2+ and VC inhibited osteophyte formation and expressions of pain-related neuropeptides. CONCLUSIONS: Intra-articular administration of Mg2+ and VC additively alleviates joint destruction and pain in OA. Our current formulation may be a cost-effective alternative treatment for OA.

Magnesium-pretreated periosteum for promoting bone-tendon healing after anterior cruciate ligament reconstruction.

Periosteum can improve tendon-bone healing when applied to wrap the tendon graft in both animal studies and clinical trials. As magnesium (Mg) ions can significantly elevate the levels of relevant cytokines involving in the osteogenic differentiation of periosteum-derived stem cells, the Mg-pretreated periosteum may be an innovative approach for enveloping the tendon graft. To test this hypothesis, we compared the effects of Mg-pretreated periosteum (M - P) and the stainless steel (SS)-pretreated periosteum (SS-P) in ACL reconstruction. We firstly found that the released Mg ions from the Mg implants were partially accumulated in periosteum, resulting in higher Mg/Ca ratio in the M - P compared to the SS-P. Additionally, the M - P showed significantly higher expression levels of calcitonin gene-related peptide (CGRP) and periostin than the SS-P due to the decrease in Cathepsin K (CTSK). Elevation of CGRP and periostin was beneficial for the osteogenic differentiation of periosteum-derived stem cells. More importantly, we demonstrated that the M - P remarkably increased the formation of fibrocartilage at the interface between the periosteum and tendon. Collectively, M - P group demonstrated significantly prevented peri-tunnel bone loss, more osseous ingrowth into the tendon graft and higher maximum load to failure as compared to the SS-P group. In summary, our study warrants further investigations for translating the current proof-of-concept findings to optimize the delivery of CGRP, periostin, and cells as novel practical therapeutic strategy for enhancing tendon-bone interface healing in patients undergoing ACL reconstruction.

Cinnamaldehyde Inhibits Inflammation of Human Synoviocyte Cells Through Regulation of Jak/Stat Pathway and Ameliorates Collagen-Induced Arthritis in Rats.

Cinnamaldehyde (Cin), a bioactive cinnamon essential oil from traditional Chinese medicine herb Cinnamomum cassia, has been reported to have multipharmacological activities including anti-inflammation. However, its role and molecular mechanism of anti-inflammatory activity in musculoskeletal tissues remains unclear. Here, we first investigated the effects and molecular mechanisms of Cin in human synoviocyte cells. Then in vivo therapeutic effect of Cin on collagen-induced arthritis (CIA) also studied. Cell Counting Kit CCK-8 assay was performed to evaluate the cell cytotoxicity. Proinflammatory cytokine expression was evaluated using quantitative polymerase chain reaction and ELISA. Protein expression was measured by western blotting. The in vivo effect of Cin (75 mg/kg per day) was evaluated in rats with CIA by gavage administration. Disease progression was assessed by clinical scoring, radiographic, and histologic examinations. Cin significantly inhibited interleukin (IL)-1ß-induced IL-6, IL-8, and tumor necrosis factor-α release from human synoviocyte cells. The molecular analysis revealed that Cin impaired IL-6-induced activation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 1 (STAT1), and STAT3 signaling pathway by inhibiting the phosphorylation of JAK2, STAT1, and STAT3, without affecting NF-κB pathway. Cin reduced collagen-induced swollen paw volume of arthritic rats. The anti-inflammation effects of Cin were associated with decreased severity of arthritis, joint swelling, and reduced bone erosion and destruction. Furthermore, serum IL-6 level was decreased when Cin administered therapeutically to CIA rats. Cin suppresses IL-1ß-induced inflammation in synoviocytes through the JAK/STAT pathway and alleviated collagen-induced arthritis in rats. These data indicated that Cin might be a potential traditional Chinese medicine-derived, disease-modifying, antirheumatic herbal drug. SIGNIFICANCE STATEMENT: In this study, we found that cinnamaldehyde (Cin) suppressed proinflammatory cytokines secretion in rheumatology arthritis synoviocyte cells by Janus kinase/signal transducer and activator of transcription pathway. The in vivo results showed that Cin ameliorated collagen-induced arthritis in rats. These findings indicate that Cin is a potential traditional Chinese medicine-derived, disease-modifying, antirheumatic herbal drug.

Dynamic and Cell-Infiltratable Hydrogels as Injectable Carrier of Therapeutic Cells and Drugs for Treating Challenging Bone Defects.

Biopolymeric hydrogels have been widely used as carriers of therapeutic cells and drugs for biomedical applications. However, most conventional hydrogels cannot be injected after gelation and do not support the infiltration of cells because of the static nature of their network structure. Here, we develop unique cell-infiltratable and injectable (Ci-I) gelatin hydrogels, which are physically cross-linked by weak and highly dynamic host-guest complexations and are further reinforced by limited chemical cross-linking for enhanced stability, and then demonstrate the outstanding properties of these Ci-I gelatin hydrogels. The highly dynamic network of Ci-I hydrogels allows injection of prefabricated hydrogels with encapsulated cells and drugs, thereby simplifying administration during surgery. Furthermore, the reversible nature of the weak host-guest cross-links enables infiltration and migration of external cells into Ci-I gelatin hydrogels, thereby promoting the participation of endogenous cells in the healing process. Our findings show that Ci-I hydrogels can mediate sustained delivery of small hydrophobic molecular drugs (e.g., icaritin) to boost differentiation of stem cells while avoiding the adverse effects (e.g., in treatment of bone necrosis) associated with high drug dosage. The injection of Ci-I hydrogels encapsulating mesenchymal stem cells (MSCs) and drug (icaritin) efficiently prevented the decrease in bone mineral density (BMD) and promoted in situ bone regeneration in an animal model of steroid-associated osteonecrosis (SAON) of the hip by creating the microenvironment favoring the osteogenic differentiation of MSCs, including the recruited endogenous cells. We believe that this is the first demonstration on applying injectable hydrogels as effective carriers of therapeutic cargo for treating dysfunctions in deep and enclosed anatomical sites via a minimally invasive procedure.

Jingshu Keli attenuates cervical spinal nerve ligation-induced allodynia in rats through inhibition of spinal microglia and Stat3 activation.

BACKGROUND CONTEXT: Cervical radicular pain resulting from mechanical compression of a spinal nerve secondary to spinal degenerative alternations negatively impacts patients' quality of life. Jingshu Keli (JSKL), a traditional Chinese medicine formula with multiple active compounds, has been prescribed for pain management in patients with cervical radiculopathy for decades. Two major components of JSKL, ferulic acid and cinnamaldehyde, were identified to have anti-inflammation effect via inhibiting activation of Stat3. PURPOSE: To investigate the efficacy of JSKL by investigating its mechanism in attenuating cervical radiculopathy-induced mechanical allodynia via modulation activation of spinal microglia and phosphorylation of signal transducer and activator of transcription 3 (Stat3). STUDY DESIGN: An in vivo animal experiment. METHODS: Cervical radiculopathy of rats was established by C7 spinal nerve ligation (SNL) with 6-0 silk suture. The effect of postoperational daily gavage of JSKL on mechanical allodynia of rats was tested on day 3, 7, and 14 after surgery. Furthermore, spinal glial cells activation and phosphorylation of Stat3 (p-Stat3) were tested with immunofluorescence imaging and Western blot. RESULT: The JSKL significantly inhibited SNL-induced allodynia as well as microglia activation in the spinal cord on day 7 and 14 after surgery. Moreover, expression of p-Stat3 was decreased in rats with SNL and JSKL treatment in comparison with rats with SNL and vehicle treatment. CONCLUSIONS: The JSKL attenuated SNL-induced mechanical allodynia in rats. This analgesic effect might be explained by the suppression of activations of spinal microglia as well as p-Stat3. Our study provides experimental evidence for JSKL as an alternative approach to manage refractory pain in patients with cervical radiculopathy.

Atypical femoral fractures and current management.

With the rapid increase in patients receiving bisphosphonates (BPs) for treating osteoporosis, one of the clinical complications associated with its long-term use is atypical femoral fractures (AFFs). Although the absolute risk for AFFs is low and it was a consensus that AFFs were acceptable compared with the amount of osteoporotic fractures BPs have prevented, epidemiological studies have proved that BPs had a strong association with AFFs and possibly more people were going to suffer from this adverse effect with wide prescriptions of this drug. In addition, AFFs seemed to have impaired ability to heal. Thus, to understand the mechanism(s) behind AFFs is important and desirable for considering preventive measures. This article reviewed the clinical features of AFFs as well as potential underlining pathological characteristics, such as the decreased turnover rate caused by BPs that led to multiple-level alternations, e.g., changes not only at cellular and tissue levels, but also related to changes in bone micro- and macrostructure and organic/inorganic contents, leading to potentially compromised mechanical properties of cortical bone when exposed to prolonged BP therapy. Severely suppressed bone turnover may also be the underlying mechanism for impaired fracture healing in patients with AFFs. The rising concerns about the risk for AFFs in nonosteoporotic patients receiving high-dose BPs to treat cancers were also discussed. Detailed investigation will help develop potential targeted pharmacological treatments such as parathyroid hormone. In addition, potential innovative internal fixation implants were discussed with regard to dynamic and biological fixation for enhancing AFF repair.