The impact of chronic obstructive pulmonary disease on bone strength.

Chronic obstructive pulmonary disease (COPD) is a lifestyle-related disease that develops in middle-aged and older adults, often due to smoking habits, and has been noted to cause bone fragility. COPD is a risk factor for osteoporosis and fragility fracture, and a high prevalence of osteoporosis and incidence of vertebral fractures have been shown in patients with COPD. Findings of lung tissue analysis in patients with COPD are primarily emphysema with a loss of alveolar septal walls, and the severity of pulmonary emphysema is negatively correlated with thoracic spine bone mineral density (BMD). On the other hand, epidemiological studies on COPD and fracture risk have reported a BMD-independent increase in fracture risk; however, verification in animal models and human bone biopsy samples has been slow, and the essential pathogenesis has not been elucidated. The detailed pathological/molecular mechanisms of musculoskeletal complications in patients with COPD are unknown, and basic research is needed to elucidate the mechanisms. This paper discusses the impacts of COPD on bone strength, focusing on findings in animal models in terms of bone microstructure, bone metabolic dynamics, and material properties.

DAIR in treating chronic PJI after total knee arthroplasty using continuous local antibiotic perfusion therapy: a case series study.

BACKGROUND: Antimicrobial agents are administered via intramedullary antibiotic perfusion (iMAP)/intrasoft tissue antibiotic perfusion (iSAP) to infected lesions to control osteoarticular and soft tissue infections. Continuous local antibiotic perfusion (CLAP) has been reported to be useful. This study aimed to investigate the outcomes of DAIR combined with CLAP for chronic PJI after total knee arthroplasty performed at our hospital. SUBJECTS AND METHODS: Six patients (male; one case, female; five cases, mean age 79.5 years (70-94)) underwent CLAP for chronic PJI after TKA at our hospital between July 2020 and June 2022. They were followable for at least one year after surgery. Seven months (17-219), with a mean follow-up of 24.3 months (12-36). In addition to direct debridement and insert exchange, systemic antimicrobial treatment, and CLAP with gentamicin were performed using NPWT. We investigated the organisms causing the inflammation, the duration of iMAP/iSAP implantation, the maximum daily dose of GM, the maximum GM blood concentration, and the presence or absence of GM-induced adverse events. RESULT: Two of six patients had a recurrence of infection at five weeks and five months after initial CLAP and required repeat CLAP treatment, but all patients could preserve their components. The organisms responsible for the flare-ups were MSSA in three cases: ESBL-producing E. coli, mixed MSSA and streptococcal infection, Klebsiella pneumonia in one case each, and unknown pathogens in one case. CLAP therapy for all patients was administered eight times in 6 cases: iMAP, mean: 10.0 days (5-16); iSAP, mean: 19.3 days (15-28); GM dose, mean: 162.5 mg/day (80-240); and GM blood concentration, mean: 1.4 µg/mL (0.2-5.0). Adverse events included one case of reversible acute kidney injury during CLAP in a patient with recurrent infection. DAIR with CLAP for chronic post-TKA infection can be a useful treatment option to preserve components and allow the infection to subside, provided the implant is not markedly loosened.

Development of a novel knee contracture mouse model by immobilization using external fixation.

AIMS: Several studies have used animal models to examine knee joint contracture; however, few reports detail the construction process of a knee joint contracture model in a mouse. The use of mouse models is beneficial, as genetically modified mice can be used to investigate the pathogenesis of joint contracture. Compared to others, mouse models are associated with a lower cost to evaluate therapeutic effects. Here, we describe a novel knee contracture mouse model by immobilization using external fixation. METHODS: The knee joints of mice were immobilized by external fixation using a splint and tape. The passive extension range of motion (ROM), histological and immunohistochemical changes, and expression levels of fibrosis-related genes at 2 and 4 weeks were compared between the immobilized (Im group) and non-immobilized (Non-Im group) groups. RESULTS: The extension ROM at 4 weeks was significantly lower in the Im group than in the Non-Im group (p < 0.01). At 2 and 4 weeks, the thickness and area of the joint capsule were significantly greater in the Im group than in the Non-Im group (p < 0.01 in all cases). At 2 weeks, the mRNA expression levels of the fibrosis-related genes, except for the transforming growth factor-ß1, and the protein levels of cellular communication network factor 2 and vimentin in the joint capsule were significantly higher in the Im group (p < 0.01 in all cases). CONCLUSION: This mouse model may serve as a useful tool to investigate the etiology of joint contracture and establish new treatment methods.

Case Report and Literature Review of Periprosthetic Atypical Femoral Fractures After Total Hip Arthroplasty.

We describe a case of periprosthetic femoral fracture with 5 major features of an atypical femoral fracture (AFF) and localized cortical thickening at the fracture site, which is characteristic of an AFF. An 81-year-old female patient had undergone cementless total hip arthroplasty for a right femoral neck fracture at the age of 66, and had been taking oral alendronate since then. At the age of 79, she developed spontaneous right thigh pain. Radiographs showed lateral cortical thickening and pedestal formation around the end of the femoral component. She was advised to discontinue oral alendronate and change to eldecalcitol. At the age of 81, she developed sudden severe pain when standing up from a seated position and was not able to walk. Radiographs showed a periprosthetic femoral fracture with 5 major features of AFF at the site of localized cortical thickening. We diagnosed a Vancouver type B1 periprosthetic femoral fracture. She underwent open reduction and internal fixation (ORIF) with an NCB® Periprosthetic Femur Plate System with cable grips. Daily subcutaneous injection of teriparatide and low intensity pulsed ultrasound therapy were performed to stimulate bone healing. She was able to walk without assistance at 4 months after ORIF. Radiographs showed adequate bridging callus and a disappearing fracture line. This case was diagnosed as a periprosthetic atypical femoral fracture (PAFF), because a periprosthetic fracture is excluded from the definition of AFF. Similar to AFF, PAFF exhibits poor clinical outcomes. The approach to treating PAFF should be decided after considering the pathogenesis.

Effect of estradiol on fibroblasts from postmenopausal idiopathic carpal tunnel syndrome patients.

Fibrosis of the subsynovial connective tissue (SSCT) is a characteristic finding in patients with idiopathic carpal tunnel syndrome (CTS). Idiopathic CTS frequently occurs in postmenopausal women; therefore, female steroid hormones, especially estrogens, may be involved in its development. In this study, we evaluated the effect of the estradiol on the expression of genes and proteins related to fibrosis of SSCT fibroblasts from patients with idiopathic CTS. This study included 10 postmenopausal women (mean age 76 years). Fibroblasts derived from SSCT were treated with estradiol (10-4 -10-12 M), and the expression levels of TGF-ß-responsive genes were evaluated. The relationships between the expression of untreated estrogen receptor α (ERα) and ERß and changes in gene expression due to estradiol treatment were examined by quantitative real-time polymerase chain reaction. The effects of 10-4 M estradiol on collagen type I (Col1) and collagen type III (Col3) protein expression levels were also evaluated by fluorescent staining. The relationships between ERα/ß and Col1/3 expression were evaluated by immunohistochemical staining. The reduction in Col1A1 mRNA expression due to estradiol treatment was positively correlated with ERα expression (r = 0.903, p < 0.01). At the protein level, expression of Col1 and Col3 were down-regulated. These results indicated that ERα-mediated signaling may be involved in the regulation of Col1A1, and its regulatory effect may be dependent on the ERα expression level. The accurate evaluation of ERα expression level in the SSCT of individual patients with idiopathic CTS might guide the effective use of new estrogen replacement therapy.

Disruption of the Aldehyde Dehydrogenase 2 Gene Results in No Increase in Trabecular Bone Mass Due to Skeletal Loading in Association with Impaired Cell Cycle Regulation Through p21 Expression in the Bone Marrow Cells of Mice.

Approximately 45% of people of East Asian descent have the inactive aldehyde dehydrogenase 2 (ALDH2) phenotype. The enzyme defect of ALDH2 has been found to adversely influence the risk of osteoporosis. The aim of this study was to clarify the effect of skeletal loading on trabecular bone structure and dynamics in Aldh2-disrupted mice in the absence of alcohol consumption. Four-week-old male Aldh2-/- (KO) and Aldh2+/+ (WT) mice were divided into a ground control (GC) group and a climbing exercise (CE) group in each genotype. The trabecular bone mineral density of the distal femur measured by peripheral quantitative computed tomography in the wild-type CE (WTCE) group was significantly higher than that in the wild-type GC (WTGC) group; however, there was no significant difference between the knockout CE (KOCE) and knockout GC (KOGC) groups. Bone histomorphometry revealed that osteogenic parameters were significantly increased in the WTCE group compared with the WTGC group, but not increased in the KOCE group compared with the KOGC group. Quantitative reverse transcriptase polymerase chain reaction and flow cytometry revealed that mRNA and protein expression levels of p21 were significantly decreased in the WTCE group compared with those in the WTGC group, while these differences were not observed between the KOGC and KOCE groups. This study provides the first in vivo evidence that p21 expression in the bone marrow is not decreased after skeletal loading and osteoblast differentiation is impaired in the absence of Aldh2 gene.

Correlation of alpha angle between various radiographic projections and radial magnetic resonance imaging for cam deformity in femoral head-neck junction.

PURPOSE: Radial magnetic resonance imaging (MRI) along the axis of the femoral head neck is the gold standard for detection of cam deformity of the proximal femur. This study was performed to identify which plain radiographic projection was best correlated with radial MRI. METHODS: Five different plain radiographic projections and 18 slices of radial MRI were applied to 35 consecutive hips with groin pain and positive impingement sign. Alpha angles were measured to detect the asphericity of the femoral head-neck junction in all images. Radiographs were taken in anteroposterior pelvis, cross-table lateral, 90° Dunn, 45° Dunn and modified 45° Dunn views. Pearson's correlation coefficients were determined to assess the association between the alpha angle obtained from radial MRI and each radiographic technique. The sensitivity, specificity, positive and positive predictive values and accuracy of plain radiographic alpha angle measurements were assessed using a threshold alpha angle value of 50.5° for cam deformity. RESULTS: Pearson's correlation coefficients in the alpha angle values between MRI and plain radiographic projections were 0.45, 0.70, 0.62, 0.81 and 0.69 for the anteroposterior pelvis, cross-table lateral, 90° Dunn, 45° Dunn and modified 45° Dunn views, respectively. In terms of sensitivity and accuracy, the 45° Dunn view had the greatest values. CONCLUSIONS: Alpha angle of the 45° Dunn view was best correlated with that of radial MRI. The 45° Dunn view had better sensitivity and accuracy than other radiographic projections. The 45° Dunn view may be preferable for screening of cam deformity. LEVEL OF EVIDENCE: II.

Optimizing the Approach to STA-MCA Bypass Surgery and Reducing Wound Complications.

BACKGROUND AND OBJECTIVES: The treatment of complex intracranial aneurysms with bypass surgery using 2 branches of the superficial temporal artery (STA) proves to be an effective surgical option. However, the harvest of these 2 STA branches, combined with a pterional craniotomy, carries the potential risk of delayed wound healing of the skin flap. This study undertook a retrospective analysis to examine and identify the factors associated with this delayed wound healing. METHODS: A total of 56 consecutive cases, including both ruptured and unruptured complex intracranial aneurysms, that underwent bypass surgery with 2 branches of the STA, were analyzed retrospectively. RESULTS: Major delayed wound healing was observed in 6 (10.7%) cases. Univariate analysis demonstrated significant associations with the following factors: rupture (P = 0.023), presence of diabetes mellitus (P = 0.028), large craniotomy size (P = 0.012), and the type of skin incision (P ≤ 0.001). Age (P = 0.283), sex (P = 0.558), body mass index (P = 0.221), and other blood test parameters did not demonstrate any statistical significance. Similarly, the presence of a dominant frontal branch (P = 0.515) or a low-positioned frontal branch (P = 0.622) did not reveal statistically significant results. CONCLUSIONS: In the treatment of complex intracranial aneurysms, where harvesting of the 2 STA branches is involved with a pterional craniotomy, producing a smaller skin flap (L- or T-shaped incision) is effective in minimizing the risk of delayed wound healing. The process of harvesting the STA and closing the wound demands meticulous care, taking into consideration the normal anatomical structures and the subdermal vascular plexus of the scalp.

A case of anterior choroidal artery occlusion test under MEP monitoring for a recurrent internal carotid artery-anterior choroidal artery bifurcation aneurysm clipping.

A 59-year-old female with recurrent Anterior Choroidal Artery (AchA) aneurysm was elected for surgery at our institution through a standard pterional approach. Two thin perforating branches were found to origin from the dome of the aneurysm during operation, and therefore complete aneurysm clipping preserving these branches was not feasible. These perforating branches were temporarily occluded under motor-evoked potential (MEP) monitoring. The MEPs remained stable during 10 min of temporary clipping, and we concluded that these branches could be sacrificed, and therefore neck clipping was performed occluding these tiny AchA perforators. Although postoperative magnetic resonance imaging with diffusion-weighted images showed ischemic signs in left AchA territory after the operation, the patient remained asymptomatic and was discharged home with mRS 0.

A case of facial nerve palsy caused by severe head injury treated by translabyrinthine approach.

Background: Several treatments for traumatic facial paralysis have been reported, but the role of surgery is still controversial. Case Description: A 57-year-old man was admitted to our hospital with head trauma due to a fall injury. A total body computed tomography (CT) scan showed a left frontal acute epidural hematoma associated with a left optic canal and petrous bone fractures with the disappearance of the light reflex. Hematoma removal and optic nerve decompression were performed immediately. The initial treatment was successful with complete recovery of consciousness and vision. The facial nerve paralysis (House and Brackmann scale grade 6) did not improve after medical therapy, and thus, surgical reconstruction was performed 3 months after the injury. The left hearing was lost entirely, and the facial nerve was surgically exposed from the internal auditory canal to the stylomastoid foramen through the translabyrinthine approach. The facial nerve's fracture line and damaged portion were recognized intraoperatively near the geniculate ganglion. The facial nerve was reconstructed using a greater auricular nerve graft. Functional recovery was observed at the 6-months follow-up (House and Brackmann grade 4), with significant recovery in the orbicularis oris muscle. Conclusion: Interventions tend to be delayed, but it is possible to select a treatment method of the translabyrinthine approach.

Carotid artery dissection due to elongated styloid process treated by acute phase carotid artery stenting: A case report.

Background: Eagle's syndrome is famous for one of the causes of internal carotid artery dissection. The treatment strategy for the illness, however, is not well established. Here, we report a case of internal carotid dissection due to an elongated styloid process successfully treated by carotid artery stenting (CAS). Case Description: A 72-year-old male with temporary dysarthria and consciousness disorder was diagnosed to suffer from multiple cerebral infarctions due to Eagle's syndrome. A cerebral blood flow (CBF) study revealed decreased blood flow and a CAS was performed 15 days after admission to preserve antegrade blood flow, resulting in full recovery of the affected CBF. Conclusion: We reported a case of vascular Eagle's syndrome in which the patient showed fluctuated neurological deficits successfully treated by CAS. Our experience suggests that cases of vascular Eagle's syndrome due to hemodynamic stress can be treated by CAS.

Potential of Continuous Local Antibiotic Perfusion Therapy for Fracture-Related Infections.

INTRODUCTION: Fracture-related infections (FRIs) are challenging for orthopedic surgeons, as conventional surgical treatment and systemic antimicrobial therapy cannot completely control local infections. Continuous local antibiotic perfusion (CLAP) is a novel and innovative therapy for bone and soft-tissue infections, and is expected to eradicate biofilms by maintaining a sustained high concentration of antimicrobial agents at the infected site. If CLAP therapy can eradicate infection even in cases with implants while preserving the implants, it would be an ideal and effective treatment for local refractory infections. This study aimed to evaluate the usefulness of novel CLAP therapy for FRIs. METHODS: Nine patients treated with CLAP therapy were retrospectively analyzed. The mean age was 65.9 (43-82) years, and the mean follow-up period was 14.9 (6-45) months. In all cases, the infected sites were related to the lower extremities (tibia, n = 6; fibula, n = 1; hip joint, n = 1; foot, n = 1). All patients underwent similar procedures for this therapy combined with negative-pressure wound therapy after thorough irrigation and debridement of infected tissues. RESULTS: The pathogens identified were Staphylococcus aureus (methicillin-resistant S. aureus, n = 5; methicillin-susceptible S. aureus, n = 1), Pseudomonas aeruginosa (n = 3), Enterococcus faecalis (n = 2), Corynebacterium (n = 1), and Enterobacter (n = 1); pathogens were not detected in one case. The mean duration of CLAP was 17.0 (7-35) days. In all cases, implants were preserved until bone union was achieved. Five cases relapsed; however, infection was finally suppressed in all cases by repeating this method. No side effects were observed. CONCLUSION: This novel case series presents treatment outcomes using CLAP therapy for FRIs. This method has the potential to control the infection without removing the implants, because of the sustained high concentration of antimicrobial agents at the infected site, and could be a valuable treatment option for refractory FRIs with implants, in which bone union has not been achieved.

Sylvian Hematoma Removal after the Stent-Retriever Thrombectomy Accompanied by Arteriole Avulsion: Case Report.

Objective: We describe an instructive case of post-thrombectomy subarachnoid hemorrhage (PTSAH) by sylvian hematoma removal. Case Presentations: An 83-year-old female presented with an acute cardiogenic right M1 occlusion. After the thrombectomy with combined stent retriever and aspiration technique with total five passes, TICI 2b reperfusion was achieved; however, CT imaging displayed subarachnoid hematoma (SAH) along the right sylvian fissure. Throughout the approach, contrast extravasation was not confirmed. The SAH grew up to become the sylvian hematoma; therefore, removal of the sylvian hematoma was conducted. An abrupt arteriole tear around the distal M2 of parietal artery was confirmed as bleeding point and those teared arteriole's stumps were electrically coagulated not to re-bleed. Conclusion: We suggest that the PTSAH is possible even in invisible-extravasation cases and the sylvian hematoma removal is effective to elucidate the etiology of the PTSAH, and is a reliable method to prevent the re-bleeding and is anticipated to improve the prognosis. Craniotomy is required for medically resistant PTSAH after thrombectomy, and avulsion of the pial artery can be the cause.

Microsurgical embolectomy with superficial temporal artery-middle cerebral artery bypass for acute internal carotid artery dissection: A technical case report.

BACKGROUND: Dissection of the internal carotid artery (ICA) is an important cause of stroke. Intravenous alteplase administration and mechanical thrombectomy have been strongly recommended for selected patients with acute ischemic stroke. However, the efficacy and safety of these treatments for ischemic stroke due to ICA dissection remain unclear. Here, we report a case of acute ICA dissection successfully treated by microsurgical embolectomy. CASE DESCRIPTION: A 40-year-old man presented with sudden left hemiparesis and in an unconscious state, with a National Institutes of Health Stroke Scale score of 14. Preoperative radiologic findings revealed an ICA dissection from the extracranial ICA to the intracranial ICA and occlusion at the superior-most aspect of the ICA. A dissection at the superior-most aspect of the ICA occlusion could not be confirmed; therefore, a surgical embolectomy with bypass was initiated. It became apparent that the superior ICA occlusion was not due to dissection but rather to an embolic occlusion; therefore, we undertook a surgical embolectomy and cervical ICA ligation with a double superficial temporal artery-middle cerebral artery bypass. The postoperative course was uneventful and, at the 6-month follow-up, the Modified Rankin Scale score for this patient was 1. CONCLUSION: Surgical embolectomy with or without bypass can safely treat acute ischemic stroke due to an ICA dissection that cannot be distinguished between a dissecting occlusion and an embolic occlusion. Thus, it may be considered as an alternative option for patients in whom mechanical thrombectomy has failed or for those who are ineligible for mechanical thrombectomy.

Performance of two bone substitutes of novel cotton-like ß-TCP/PDLGA and granular ß-TCP on bone regeneration in the femoral bone defect of the Beagle dogs.

This study aimed to clarify whether novel cotton-like composite made of ß-tricalcium phosphate (ß-TCP) and poly(Dl-lactide-co-glycolide) (PDLGA) has a different effect on in vivo bone regeneration after bone defect than that of granular ß-TCP. Five male Beagle dogs served as subjects. Cortical and medullary bone defect as non-through holes were made at the diaphysis of the bilateral femurs. One side was implanted with ß-TCP/PDLGA (ß-TCP/PDLGA group) and the other side was implanted with granular ß-TCP (ß-TCP group). At 4 weeks after implantation, we found no significant differences in the percentages of newly formed bone area and fibrous tissue area in the bone defect between the two groups. The ß-TCP/PDLGA group showed more uniform filling on the surface and earlier disappearance of the material in the medullary region, and there were fewer inflammatory cells and osteoclasts in the bone defect in the ß-TCP/PDLGA group. In conclusion, ß-TCP/PDLGA performs better at filling the bone defect uniformly and disappears earlier at the cortical and medullary regions while causing less inflammation and bone resorption. Although bone formation activity of the ß-TCP/PDLGA group in the cortical region was lower, the newly formed bone volume in bone defect of the ß-TCP/PDLGA group was equal to that of the ß-TCP group.

Chronic obstructive pulmonary disease severity in middle-aged and older men with osteoporosis associates with decreased bone formation.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a risk factor for osteoporosis. Nevertheless, much remains unclear regarding the bone metabolism dynamics associated with COPD. The present study focuses on the associations between the COPD severity and serum bone metabolism biomarkers. METHODS: We enrolled 40 patients who visited the orthopedics departments at our institutions and underwent dual-energy X-ray absorptiometry between September 2015 and December 2017. Only male osteoporosis patients over 45 years of age were included, and 5 patients were excluded due to disease or use of internal medicines affecting bone metabolism. All subjects underwent lung function testing, spine radiography, and blood tests. We measured percent forced expiratory volume in 1 second (%FEV1), which reflects COPD severity, and we examined the relationships between %FEV1 and serum levels of bone metabolism biomarkers. RESULTS: All subjects were diagnosed with osteoporosis based on T-scores. %FEV1 correlated with body weight, body mass index (BMI), and Z-score/T-scores. %FEV1 moderately correlated with serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b in the partial correlation analysis adjusted for BMI or T-score in the lumbar vertebrae. We performed a hierarchical multiple regression analysis to identify that serum ALP and P1NP were the independent explanatory variables to %FEV1 independent of other factors. CONCLUSIONS: The data suggest that the COPD severity in middle-aged and older men with osteoporosis associates with decreased bone formation. COPD patients may exhibit bone metabolism dynamics characterized by low bone turnover with osteogenesis dysfunction as COPD becomes severe.

Disruption of the aldehyde dehydrogenase 2 gene increases the bone anabolic response to intermittent PTH treatment in an ovariectomized mouse model.

Aldehyde dehydrogenase 2 (ALDH2) is the enzyme that oxidizes the acetaldehyde produced by alcohol metabolism. This variant not only affects the response to alcohol but is also associated with several diseases, such as esophageal cancer, myocardial infarction, and particularly osteoporosis. In our previous study, we reported that compared to wild-type (WT) mice, Aldh2 knockout (KO) mice naturally have a strong bone formation ability, and high expression of parathyroid hormone receptor (PTHR1) in osteocytes. The effect of the Aldh2 gene on bone metabolism in response to intermittent PTH treatment is unknown. The purpose of this study was to clarify the effect of the Aldh2 gene on the bone anabolic response to intermittent PTH treatment in ovariectomized mice. Female KO and WT mice were ovariectomized at 8 weeks of age. At 14 weeks of age, the KO and WT mice were divided into vehicle-treated (Veh) and PTH-treated (PTH) groups (i.e., the WT-Veh, WT-PTH, KO-Veh and KO-PTH groups). PTH (1-34) and vehicle were subcutaneously administered to each group at a dose of 40 µg/kg body weight (BW) five times per week for 4 weeks. Micro-CT showed that the bone volume (BV), trabecular number (Tb.N), connectivity density (Conn.D), and cortical thickness (Ct.Th) values in the KO-PTH mice were significantly higher than those in the KO-Veh mice. Histomorphometric analysis showed that the BV, Tb.N, and mineral apposition rate (MAR) values in the KO-PTH group were significantly higher than those in the KO-Veh group. The mRNA expression level of PTHR1 in the KO-PTH group was significantly increased and that of p21 in the KO-PTH group was significantly decreased compared with the levels in the KO-Veh group. The expression of PTHR in osteocytes from the KO-PTH group was also significantly increased compared with that in osteocytes from the KO-Veh group. Furthermore, cell cultures revealed that the ALP+CFU-f/total CFU-f percentage was significantly higher in the KO-PTH group than in the KO-Veh group. We concluded that in ovariectomized Aldh2 KO mice, the bone anabolic response to intermittent PTH treatment was significantly enhanced compared to that in WT mice, which may be mediated by the high expression level of PTHR1.

Attenuation of Post-Traumatic Osteoarthritis After Anterior Cruciate Ligament Injury Via Inhibition of Hedgehog Signaling.

We aimed to investigate whether post-traumatic osteoarthritis (PTOA) progression is appropriately represented by a PTOA mouse model using a unique climbing cage to add mechanical loading after anterior cruciate ligament (ACL) transection and to determine how Hedgehog signaling inhibition prevents PTOA progression by observing time-dependent morphological changes. This controlled laboratory study histologically compared mice with surgically-induced ACL transection (ACLT) and those with voluntary increased activity in a climbing cage from 1 week postoperatively (ACLT + climbing). We generated conditional knockout (cKO) mice with a deleted Smoothened (Smo) gene. Time-dependent histopathological, immunohistochemical, and gene expression analyses were performed. The ACLT + climbing group showed more severe cartilage defects and massive osteophyte formation than the ACLT group. Smo deletion significantly suppressed PTOA progression. The time-dependent assessment revealed cartilaginous processes of equivalent size at the posterior tibial margin in the Smo cKO and control mice at 4 weeks postoperatively. However, at 8 weeks postoperatively, mature ossifying lesions were detected in the controls but not in Smo cKO mice. In the articular cartilage, ADAMTS5 and RUNX2 expression were observed in hypertrophic chondrocytes near the defective cartilage in controls but not in Smo cKO mice. Climbing exercise after ACLT accelerated PTOA progression more severely not only through increasing joint instability induced by ACLT but also through mechanical loading force induced by climbing exercise. Hedgehog signaling inhibition attenuated PTOA progression by suppressing chondrocyte hypertrophy induced by mechanical loads, to which ACL-deficient athletes are usually exposed. Thus, Hedgehog signaling inhibition may be a therapeutic option to prevent arthritic changes in athletes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:609-619, 2020.

Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice.

Calcium balance is important in bone homeostasis. The transient receptor potential vanilloid (TRPV) channel is a nonselective cation channel permeable to calcium and is activated by various physiological and pharmacological stimuli. TRPV1 and TRPV4, in particular, have important roles in intracellular Ca2+ signaling and extracellular calcium homeostasis in bone cells. TRPV1 and TRPV4 separately mediate osteoclast and osteoblast differentiation, and deficiency in any of these channels leads to increased bone mass. However, it remains unknown whether bone mass increases in the absence of both TRPV1 and TRPV4. In this study, we used TRPV1 and TRPV4 double knockout (DKO) mice to evaluate their bone mass in vivo, and osteoclast and osteoblast differentiation in vitro. Our results showed that DKO mice and wild type (WT) mice had no significant difference in body weight and femur length. However, the results of dual-energy X-ray absorption, microcomputed tomography, and bone histomorphometry clearly showed that DKO mice had higher bone mass than WT mice. Furthermore, DKO mice had less multinucleated osteoclasts and had lower bone resorption. In addition, the results of cell culture using flushed bone marrow from mouse femurs and tibias showed that osteoclast differentiation was suppressed, whereas osteoblast differentiation was promoted in DKO mice. In conclusion, our results suggest that the increase in bone mass in DKO mice was induced not only by the suppression of osteoclast differentiation and activity but also by the augmentation of osteoblast differentiation and activity. Our findings reveal that both the single deficiency of TRPVs and the concurrent deficiency of TRPVs result in an increase in bone mass. Furthermore, our data showed that DKO mice and single KO mice had varying approaches to osteoclast and osteoblast differentiation in vitro, and therefore, it is important to conduct further studies on TRPVs regarding the increase in bone mass to explore not only individual but also a combination of TRPVs.