Distinct patterns of cytokines, chemokines, and growth factors in synovial fluid after ACL injury in comparison to osteoarthritis.

This study analyzed knee synovial fluid after anterior cruciate ligament (ACL) tear and in osteoarthritis (OA) to test the hypotheses that concentrations of cytokines, chemokines, and growth factors differ (a) by diagnosis and (b) after ACL tear by time from injury and presence/absence of concomitant meniscus tear. Synovial fluid samples were collected from two groups, ACL tears (with or without meniscus tear) (N = 13) and Kellgren-Lawrence grade 3 and 4 OA (N = 16), undergoing clinically indicated aspiration of the knee joint. Multiple cytokines, chemokines, and growth factors were assessed using a multiplexed 45-protein panel. Comparisons were made for the concentrations of all molecules between ACL tear and OA patients, isolated versus combined ACL and meniscus tears, and categorized by time from injury: acute or early subacute (<15 days, N = 8) versus late subacute or chronic (>15 days and <3 months, N = 5). ACL tear patients have higher levels of six molecules (IL-4, IL-5, IL-13, PlGF-1, bNGF, TNF-α) in knee synovial fluid compared to OA patients. Isolated ACL tears express higher levels of IL-4, IL-13 and IFN-γ and lower levels of IL-7 than ACL tears with a concomitant meniscus tear. SDF-1α, PlGF-1, IL-1RA, HGF, bNGF, and BDNF levels are elevated immediately after injury and drop off significantly in the late subacute phase (after 15 days). Synovial fluid from knees with ACL tears have elevated metabolic activity compared to knees with OA. The cytokine profiles after ACL tears are influenced by the time from injury and the presence of meniscus tears. These findings offer valuable insights into the levels of cytokines, chemokines, and growth factors in the knee after ACL injury, information which may have important implications for the diagnosis, prognosis and treatment of this common pathology.

Patients' Characteristics Can Predict Clinical Outcomes Following Hip Arthroscopy by Reflecting the Patterns of Labral Tears: A Retrospective Observational Study.

PURPOSE: To evaluate the relationship between morphological differences in labral tears and clinical features of the hip joint in patients who underwent hip arthroscopy. MATERIALS AND METHODS: We retrospectively analyzed data from patients who underwent arthroscopic surgery for the treatment of labral tears. Hip labral tears were morphologically classified as longitudinal peripheral tears (group L), radial fibrillated tears (group FI), radial flaps (group FL), and an unstable labrum (group U). Radiographically, the center-edge angle, acetabular roof obliquity, vertical-center-anterior angle, alpha angle, femoral head-neck offset ratio, and crossover sign were evaluated and compared among the groups. The relationship between labral morphology and these radiographic findings, as well as clinical findings, such as age, gender, preoperative range of hip motion, and the clinical outcomes using modified Harris Hip Score (mHHS) were also examined. RESULTS: This study included fifty patients. Groups L and FI were often observed in late middle-aged patients with relatively shallow acetabular coverage. Group FL tears were frequently observed in young males with radiographic features, such as femoroacetabular impingement (FAI), compared to the other groups. Group U comprised mostly young females with relatively shallow acetabular coverage compared to the other groups. For the postoperative mHHS, group FL showed the best score among all groups, with a significant difference between groups FL and FI (p = 0.034). CONCLUSIONS: Our study revealed that morphologically, different labral tears were associated with different clinical features and radiological findings. Especially, our study can provide predictive findings for hip arthroscopists that younger males with FAI show better clinical outcomes when compared to middle-aged females with shallow acetabulum, which is indicative of degenerative hip labral tears. LEVEL OF EVIDENCE: IV case series.

Posterior Ankle Arthroscopy for Flexor Hallucis Longus Entrapment: A Case Report.

INTRODUCTION: Stenosing tenosynovitis is a chronic disorder frequently observed in finger triggering of a digit. Regarding the toes, although entrapment of the flexor hallucis longus (FHL) has already been reported in a few cases among sports players, the clinical condition is uncommon. Besides, the case without any specific causes is particularly rare. CASE REPORT: We report the case of a 26-year-old male with FHL entrapment. Even though he was unaware of any cause, he felt tenderness on the posteromedial side of his left ankle, and his great toe was locked in the flex position. Magnetic resonance imaging indicated effusion in the tendon sheath of the FHL and the possibility of a partial tear of the FHL. We hypothesized that the scar tissue secondary to the partial tear of the FHL may have been irritated at the retrotalar pulley below the sustentaculum tali, where the FHL glides. Therefore, posterior ankle arthroscopy was performed for the treatment of the FHL entrapment. CONCLUSION: Orthopedic surgeons should list this pathology as a differential diagnosis of posterior ankle pain, even in non-athletes.

Conventional computed tomography software can be used for accurate pre-operative templating in bipolar hip arthroplasty: A preliminary report.

BACKGROUND: The aim of this study was to investigate the use of pre-operative templating for bipolar hip arthroplasty (BHA) for displaced femoral neck fracture using multiplanar reconstruction (MPR) of computed tomography (CT) images. METHODS: Nineteen patients who underwent BHA were enrolled in this study. For pre- and post-operative evaluation, a CT scan was performed from the pelvis to the knee joints. MPR of the CT image was done using software to measure the femoral head cup diameter, offset, stem size, length of the modular neck, distance from the neck osteotomy, and femoral anteversion. We compared these parameters pre- and post-operatively. RESULTS: Both the femoral head cup diameter and length of the modular neck were found to be significantly different between pre- and post-operative measurements, although the differences were minor. Other parameters, including the femoral offset, were not significantly different between the pre- and post-operative measurements. The size of the femoral stem, cup diameter, and length of the modular neck were consistent with the planned size and accurate (within ±1 size) in more than 84% cases. CONCLUSION: Our pre-operative templating approach for BHA using MPR of CT has potential clinical utility as a complementary tool for pre-operative planning using three-dimensional templating software. Moreover, this technique could be feasible in most hospitals without additional expenditure.

A Novel Technique of Arthroscopic Ankle Lateral Ligament Repair Using a Knotless Suture Anchor.

BACKGROUND: Although arthroscopic lateral ligament repair (ALLR) with suture anchors for chronic lateral ankle instability has become widely accepted, some complications have been reported as well. Establishment of a new technique is essential for better clinical outcomes after ALLR. PURPOSE: To report a novel technique and good clinical results of ALLR using a knotless suture anchor. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We examined 30 patients (16 men and 14 women) who underwent ALLR. The mean age of the patients was 30.0 years, and the average period of postoperative monitoring was 21 months. The Japanese Society for Surgery of the Foot (JSSF) ankle-hindfoot scale was used for clinical evaluation postoperatively, and the Self-Administered Foot Evaluation Questionnaire (SAFE-Q) for patient-reported results. Surgical complications were also examined. RESULTS: The JSSF ankle-hindfoot scale showed a significant improvement from preoperatively to follow-up (from 72.1 to 96.1; P < 0.001), and the SAFE-Q was significantly improved in all subscales (pain and pain-related, physical function and daily living, social function, shoe-related, and general health and well-being; P < 0.004 for all). Complications included residual joint pain due to remaining osteophytes in 1 case, scar pain of the accessory anterolateral portal in 2 cases, and positive Tinel sign indicative of superficial peroneal nerve irritation at the anterolateral portal in 1 case. CONCLUSION: The clinical results of the novel ALLR technique were overall satisfactory. Knot-related complications, one of the main reasons for postoperative complications, were reduced by using a knotless suture anchor.

Prediction of intra-articular pathology and arthroscopic outcomes for femoroacetabular impingement and labral tear based on the response to preoperative anaesthetic hip joint injections.

OBJECTIVE: This study investigated whether the preoperative response to intra-articular injections is associated with intra-articular pathological findings and arthroscopy outcomes. METHODS: This study included 49 patients who underwent arthroscopic hip surgery for femoroacetabular impingement and labral tear after receiving preoperative hip joint injections. The response to anaesthetic injections was categorized as poor (0-50%) or good (51-100%). With respect to anatomical indices, we evaluated the lateral centre-edge angle (LCEA), acetabular roof obliquity (ARO), vertical-centre-anterior angle (VCA), and the alpha angle (on a lateral view). We evaluated the association between these indices (including the types of hip labral tears and cartilage damage) and the effectiveness of intra-articular injections. RESULTS: The study included 22 men and 27 women, and the mean age of patients was 36.4 years. No statistically significant association was observed between the response to preoperative anaesthetic hip joint injections and patient demographics (age, sex) and anatomical indices (LCEA, ARO, VCA, and alpha angle) (p > 0.05). All patients showed labral damage; however, labral tear classification or cartilage damage was not significantly associated with the effectiveness of joint injections. At the 1-year post-operative follow-up, patients with a good response to anaesthetic hip joint injections showed a significantly better outcome than patients with a poor response to these injections (p < 0.01). CONCLUSION: The response to preoperative anaesthetic hip joint injections may indicate the presence of intra-articular pathology. Furthermore, this association may have predictive value in determining post-operative outcomes following hip arthroscopy.

Does the duration to bipolar hip arthroplasty for femoral neck fracture influence on postoperative muscular strength?

BACKGROUND: The primary purpose of this study was to compare the postoperative muscular strength and functional performance between early versus late bipolar hip arthroplasty (BHA) intervention for femoral neck fracture classified by the duration from the onset to surgery. METHODS: Twenty-one patients who could walk at 12 months or more after BHA were enrolled into this study. We examined the muscular strength of hip flexion, extension, abduction, and knee extension of these patients. Time of one-leg standing, timed up and go test, pain grade by visual analog scale, and Barthel index were also evaluated as functional indices. We classified these patients into two groups by the duration from the onset to surgery, namely: within 3 days until BHA (early OP) and more than 4 days (late OP) to compare these indices at the latest follow-up. RESULTS: The mean days until operation were 2.3 days in the early-OP group and 5.9 days in the late-OP group, showing a significant difference between the two groups. Muscular strength and other functional indices were also found to have no significant differences between these two groups. CONCLUSION: Our study suggests that the delay to operate might not severely compromise the muscular strength around the hip joint for least 1.5 years among ambulatory patients.

Denosumab Treatment Improved Health-Related Quality of Life in Osteoporosis: A Prospective Cohort Study.

Improving patient health-related quality of life (HRQOL) and prevention of bone fracture are important components of the treatment of osteoporosis. Our aim in this study was to evaluate the effect of denosumab treatment in improving HRQOL among patients with osteoporosis. Our analysis was based on 332 patients with osteoporosis, followed for 24 months. All patients received denosumab (60 mg) subcutaneously every 6 months. Bone mineral density (BMD) was assessed at the distal radius, with serum concentration of calcium, phosphate, P1NP, and TRACP5b also measured. HRQOL assessment included pain (visual analogue scale [VAS]) and the EQ-5D questionnaire. A multivariate analysis was performed to identify the possible confounders associated with deterioration in the EQ-5D utility score in response to denosumab treatment. Denosumab treatment yielded a 3.4% increase in BMD at 24 months. Serum levels of TRACP5b and P1NP decreased significantly, from baseline, at 6 months, with no effect on calcium and phosphate levels. Pain VAS and EQ-5D utility score improved significantly, from baseline, at 6 months, with the EQ-5D utility score correlating with the BMD at all time points of measurement over the 24-month period of observation. Knee osteoarthritis and multiple comorbidities were significantly associated with a worse HRQOL in response to denosumab treatment. Denosumab treatment increased BMD, with improvements in BMD correlating with improved HRQOL, supporting a possible benefit of using denosumab for the treatment of osteoporosis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Platelet-Rich Plasma Released From Polyethylene Glycol Hydrogels Exerts Beneficial Effects on Human Chondrocytes.

Osteoarthritis (OA) is a debilitating joint disease resulting from chronic joint inflammation and erosion of articular cartilage. A promising biological treatment for OA is intra-articular administration of platelet-rich plasma (PRP). However, immediate bolus release of growth factors limits beneficial therapeutic effects of PRP, thus necessitating the demand for sustained release platforms. In this study, we evaluated the therapeutic value of PRP released from a polyethylene glycol (PEG) hydrogel on articular chondrocytes/cartilage explants derived from OA patients. Lyophilized PRP (PRGF) was encapsulated in PEG hydrogels at 10% w/v and hydrogel swelling, storage modulus and degradation and PRGF release kinetics were determined. PRGF releasate from the hydrogels was collected on day 1, 4, and 11. Encapsulation of PRGF at 10% w/v in PEG hydrogels had minimal effect on hydrogel properties. PRGF was released with an initial burst followed by sustained release until complete hydrogel degradation. Effect of PRGF releasates and bolus PRGF (1% w/v PRGF) on patient-derived cartilage explants or chondrocytes was assessed by chondrocyte proliferation (pico-green assay), gene expression for COL1A1, COL2A1, MMP13, COX2, and NFKB1 (real-time polymerase chain reaction), and measurement of nitric oxide concentration (Griess' assay). Compared to bolus PRGF, PRGF releasates enhanced chondrocyte proliferation, suppressed the expression of genes like MMP13, NFKB1, COL1A1, and COL2A1 and reduced levels of nitric oxide. Taken together, these results indicate that release of PRGF from PEG hydrogels may improve the therapeutic efficacy of PRP and merits further investigation in an animal model of OA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2401-2410, 2019.

Clinical Outcomes of Total Ankle Arthroplasty With Total Talar Prosthesis.

BACKGROUND: Total ankle arthroplasty (TAA) has been developed to treat patients with end-stage ankle osteoarthritis (OA). However, there is often difficulty in treating complicated pathologies such as ankle OA with subtalar joint OA and severe talar collapse. Therefore, this study aimed to explore the short-term results and complications of TAA with total talar prosthesis, known as combined TAA, as the new techniques to treat such complicated pathology. METHODS: We examined postoperative results including ankle range of motion, Japanese Society for Surgery of the Foot (JSSF) scale, and complications. There were 22 patients (15 women), with mean follow-up of 34.9 (range, 24-53 months), and the mean age was 72 (range, 62-80) years. The main indications for combined TAA included osteoarthritis (18 patients), rheumatoid arthritis (3 patients), and talar osteonecrosis with osteoarthritis (one patient). RESULTS: The mean range of motion improved from 4.0 to 14.4 degrees in dorsiflexion and from 23.8 to 32.0 degrees in plantarflexion. The JSSF scale improved from 50.5 to 91.5 points. Prolonged wound healing occurred in 3 patients, and medial malleolus fracture occurred in 4 patients. CONCLUSION: Combined TAA was a reliable procedure for the treatment of not only ankle OA following avascular necrosis of talus but also of degeneration of both ankle and subtalar joints. LEVEL OF EVIDENCE: Level IV, case series.

Evidence for Genetic Contribution to Variation in Posttraumatic Osteoarthritis in Mice.

OBJECTIVE: Recombinant inbred mouse strains generated from an LG/J and SM/J intercross offer a unique resource to study complex genetic traits such as osteoarthritis (OA). We undertook this study to determine the susceptibility of 14 strains to various phenotypes characteristic of posttraumatic OA. We hypothesized that phenotypic variability is associated with genetic variability. METHODS: Ten-week-old male mice underwent surgical destabilization of the medial meniscus (DMM) to induce posttraumatic OA. Mice were killed 8 weeks after surgery, and knee joints were processed for histology to score cartilage degeneration and synovitis. Micro-computed tomography was used to analyze trabecular bone parameters including subchondral bone plate thickness and synovial ectopic calcifications. Gene expression in the knees was assessed using a QuantiGene Plex assay. RESULTS: Broad-sense heritability ranged from 0.18 to 0.58, which suggested that the responses to surgery were moderately heritable. The LGXSM-33, LGXSM-5, LGXSM-46, and SM/J strains were highly susceptible to OA, while the LGXSM-131b, LGXSM-163, LGXSM-35, LGXSM-128a, LGXSM-6, and LG/J strains were relatively OA resistant. This study was the first to accomplish measurement of genetic correlations of phenotypes that are characteristic of posttraumatic OA. Cartilage degeneration was significantly positively associated with synovitis (r = 0.83-0.92), and subchondral bone plate thickness was negatively correlated with ectopic calcifications (r = -0.59). Moreover, we showed that 40 of the 78 genes tested were significantly correlated with various OA phenotypes. However, unlike the OA phenotypes, there was no evidence for genetic variation in differences in gene expression levels between DMM-operated and sham-operated knees. CONCLUSION: For these mouse strains, various characteristics of posttraumatic OA varied with genetic composition, which demonstrated a genetic basis for susceptibility to posttraumatic OA. The heritability of posttraumatic OA was established. Phenotypes exhibited various degrees of correlations; cartilage degeneration was positively correlated with synovitis, but not with the formation of ectopic calcifications. Further investigation of the genome regions that contain genes implicated in OA, as well as further investigation of gene expression data, will be useful for studying mechanisms of OA and identifying therapeutic targets.

Downregulation of aquaporin 9 decreases catabolic factor expression through nuclear factor­κB signaling in chondrocytes.

Aquaporins (AQPs) are small integral membrane proteins that are essential for water transport across membranes. AQP9, one of the 13 mammalian AQPs (including AQP0 to 12), has been reported to be highly expressed in hydrarthrosis and synovitis patients. Given that several studies have identified signal transduction as an additional function of AQPs, it is hypothesized that AQP9 may modulate inflammatory signal transduction in chondrocytes. Therefore, the present study used a model of interleukin (IL)­1ß­induced inflammation to determine the mechanisms associated with AQP9 functions in chondrocytes. Osteoarthritis (OA) and normal cartilage samples were subjected to immunohistological analysis. In addition, matrix metalloproteinase (MMP)3, MMP13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS­5) mRNA and protein analysis was conducted in normal human articular chondrocytes from the knee (NHAC­Kn) stimulated with IL­1ß by reverse transcription­polymerase chain reaction (RT­qPCR) and western blotting, respectively. AQP9 knockdown was also performed by transfection of AQP9­specific small interfering RNA using Lipofectamine. AQP1, 3, 7, 9 and 11 mRNA expression levels were detected in OA human chondrocytes and in IL­1ß­treated normal human chondrocytes. The levels of AQP9, MMP­3, MMP­13 and ADAMTS­5 mRNA were increased by treatment with 10 ng/ml IL­1ß in a time­dependent manner, while knockdown of AQP9 expression significantly decreased the mRNA levels of the MMP3, MMP13 and ADAMTS­5 genes, as well as the phosphorylation of IκB kinase (IKK). Treatment with a specific IKK inhibitor also significantly decreased the expression levels of MMP­3, MMP­13 and ADAMTS­5 in response to IL­1ß stimulation. Furthermore, immunohistochemical analysis demonstrated that AQP9 and inflammatory markers were highly expressed in OA cartilage. In addition, the downregulation of AQP9 in cultured chondrocytes decreased the catabolic gene expression in response to IL­1ß stimulation through nuclear factor­κB signaling. Therefore, AQP9 may be a promising target for the treatment of OA.

Depletion of aquaporin 1 decreased ADAMTS­4 expression in human chondrocytes.

Inflammation serves an important role in the progression of osteoarthritis (OA), and IL­1ß may act as a catabolic factor on cartilage, reducing the synthesis of primary cartilage components type II collagen and aggrecan. Aquaporin 1 (AQP1) is a 28­kDa water channel formed of six transmembrane domains on the cell membrane. AQP1 is highly expressed in the anus, gallbladder and liver, and is moderately expressed in the hippocampus, ependymal cells of the central nervous system and articular cartilage. It was hypothesized that AQP1 may be highly expressed in OA cartilage and that it may increase the expression of catabolic factors during inflammatory OA progression. Therefore, the present study evaluated AQP1 functions in human OA articular chondrocytes. Primary chondrocytes were isolated from human hip and knee cartilage tissues, cultured and transfected with AQP1­specific small interfering RNA with or without subsequent IL­1ß treatment. In vitro explant culture from hip cartilages were also prepared. Reverse transcription­polymerase chain reaction (RT­PCR) was performed to assess the expression of AQP genes in human articular cartilage, AQP1 immunohistochemistry of the cartilages and explant culture, as well as RT­quantitative PCR, western blotting and immunocytochemistry/immunofluorescence of OA chondrocytes to evaluate the expression of AQP1, and catabolic and anabolic factors. RT­PCR results demonstrated that AQP0, 1, 3, 7, 9, and 11 were expressed in OA chondrocytes. Immunohistochemistry revealed that AQP1 was highly expressed in the superficial to middle zones of OA articular cartilages. Additionally, AQP1 mRNA was significantly higher in OA cartilage and IL­1ß treatment significantly increased AQP1 expression in hip explant cartilage. Furthermore, AQP1 downregulation decreased a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)­4 expression in OA chondrocytes, though it did not affect other associated genes. Immunofluorescence showed that AQP1 and ADAMTS­4 were co­localized. These findings indicated that AQP1 depletion may decrease ADAMTS­4 expression in human OA chondrocytes. Therefore, regulating AQP1 expression may be a strategy to suppress catabolic factors during OA progression.

Arthroscopic Debridement of a Talar Cyst and Bone Grafting with the Osteochondral Autograft Transfer System A Case Report.

Simple bone cysts compose approximately 3% of all primary bone tumors and most commonly occur in the metaphyseal regions of the proximal humerus and femur. The percentage of the talus with suspected bone tumors is reported to be 0.003%. Therefore, talar cysts are rare but sometimes present as aggressive lesions, and they can affect any of the tarsal bones. Recently, an arthroscopic approach to these lesions has been developed that is less invasive than conventional open surgery. In the present case study, we profile a 65-year-old female patient who received arthroscopic debridement of a bone cyst from the medial aspect of the talus with the osteochondral autograft transfer system (OATS). By using the OATS core harvester, we penetrated into the tumor. After the cylindrical bone plug was pulled out, the tumor was removed and artificial bone granules were firmly packed into the cavity with intralesional arthroscopy. Then, the cylindrical bone plug previously harvested by OATS was implanted at the site with careful precision. This intervention resulted in a relative restoration of talar dome anatomy and ultimately restored the patient to activity with minimal discomfort. Therefore, arthroscopic debridement with OATS has the potential to be a useful option in dealing with debilitating osteochondral cystic lesions.

Consecutive Bilateral Hip Arthroscopy for Symptomatic Bilateral Femoroacetabular Impingement in an Elite Rugby player: A Case Report.

We report a case of concurrent bilateral hip arthroscopy for symptomatic bilateral femoroacetabular impingement (FAI) performed under the single anesthesia on an elite rugby player. A 27-year-old rugby player who played for a top league had bilateral hip joint pain. Physical examination revealed bilateral tenderness in the anterior area of the hips, with positive impingement signs. Based on the findings of hip radiography and magnetic resonance imaging, the patient's symptoms were diagnosed as bilateral FAI with hip labral tears. Bilateral hip arthroscopy under the single anesthesia was performed due to refractory symptoms. He returned to regular rugby games without any symptoms in either hip. Bilateral hip arthroscopic surgery under the single anesthesia should be an effective treatment for typical and symptomatic FAI, even in elite athletes.

Therapeutic efficacy of intra-articular hyaluronan derivative and platelet-rich plasma in mice following axial tibial loading.

OBJECTIVE: To investigate the therapeutic potential of intra-articular hyaluronan-derivative HYADD® 4-G and/or platelet-rich plasma (PRP) in a mouse model of non-invasive joint injury. METHODS: Non-invasive axial tibial loading was used to induce joint injury in 10-week-old C57BL/6J mice (n = 86). Mice underwent a single loading of either 6 Newton (N) or 9N axial tibial compression. HYADD® 4-G was injected intra-articularly at 8 mg/mL or 15 mg/mL either before or after loading with or without PRP. Phosphate-buffered-saline was injected as control. Knee joints were harvested at 5 or 56 days post-loading and prepared for micro-computed tomography scanning and subsequently processed for histology. Immunostaining was performed for aggrecan to monitor its distribution, for CD44 to monitor chondrocyte reactive changes and for COMP (cartilage oligomeric matrix protein) as an index for cartilage matrix changes related to loading and cartilage injury. TUNEL assay was performed to identify chondrocyte apoptosis. RESULTS: Loading initiated cartilage proteoglycan loss and chondrocyte apoptosis within 5 days with slowly progressive post-traumatic osteoarthritis (no cartilage degeneration, but increased synovitis and ectopic calcification after 9N loading) at 56 days. Mice treated with repeated HYADD® 4-G (15 mg/mL) or HYADD® 4-G (8 mg/mL) ± PRP or PRP alone exhibited no significant improvement in the short-term (5 days) and long-term (56 days) consequences of joint loading except for a trend for improved bone changes compared to non-loaded joints. CONCLUSION: While we failed to show an overall effect of intra-articular delivery of hyaluronan-derivative and/or PRP in reversing/protecting the pathological events in cartilage and synovium following joint injury, some bone alterations were relatively less severe with hyaluronan-derivative at higher concentration or in association with PRP.

Post-Traumatic Osteoarthritis in Mice Following Mechanical Injury to the Synovial Joint.

We investigated the spectrum of lesions characteristic of post-traumatic osteoarthritis (PTOA) across the knee joint in response to mechanical injury. We hypothesized that alteration in knee joint stability in mice reproduces molecular and structural features of PTOA that would suggest potential therapeutic targets in humans. The right knees of eight-week old male mice from two recombinant inbred lines (LGXSM-6 and LGXSM-33) were subjected to axial tibial compression. Three separate loading magnitudes were applied: 6N, 9N, and 12N. Left knees served as non-loaded controls. Mice were sacrificed at 5, 9, 14, 28, and 56 days post-loading and whole knee joint changes were assessed by histology, immunostaining, micro-CT, and magnetic resonance imaging. We observed that tibial compression disrupted joint stability by rupturing the anterior cruciate ligament (except for 6N) and instigated a cascade of temporal and topographical features of PTOA. These features included cartilage extracellular matrix loss without proteoglycan replacement, chondrocyte apoptosis at day 5, synovitis present at day 14, osteophytes, ectopic calcification, and meniscus pathology. These findings provide a plausible model and a whole-joint approach for how joint injury in humans leads to PTOA. Chondrocyte apoptosis, synovitis, and ectopic calcification appear to be targets for potential therapeutic intervention.

Cyclin-Dependent Kinase Inhibitor-1-Deficient Mice are Susceptible to Osteoarthritis Associated with Enhanced Inflammation.

Osteoarthritis (OA) is a multifactorial disease, and recent data suggested that cell cycle-related proteins play a role in OA pathology. Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates activation of other CDKs, and recently, we reported that p21 deficiency induced susceptibility to OA induced by destabilization of the medial meniscus (DMM) surgery through STAT3-signaling activation. However, the mechanisms associated with why p21 deficiency led to susceptibility to OA by the STAT3 pathway remain unknown. Therefore, we focused on joint inflammation to determine the mechanisms associated with p21 function during in vitro and in vivo OA progression. p21-knockout (p21-/- ) mice were used to develop an in vivo OA model, and C57BL/6 (p21+/+ ) mice with the same background as the p21-/- mice were used as controls. Morphogenic changes were measured using micro-CT, IL-1ß serum levels were detected by ELISA, and histological or immunohistological analyses were performed. Our results indicated that p21-deficient DMM-model mice exhibited significant subchondral bone destruction and cartilage degradation compared with wild-type mice. Immunohistochemistry results revealed p21-/- mice susceptibility to OA changes accompanied by macrophage infiltration and enhanced MMP-3 and MMP-13 expression through IL-1ß-induced NF-κB signaling. p21-/- mice also showed subchondral bone destruction according to micro-CT analysis, and cathepsin K staining revealed increased numbers of osteoclasts. Furthermore, p21-/- mice displayed increased serum IL-1ß levels, and isolated chondrocytes from p21-/- mice indicated elevated MMP-3 and MMP-13 expression with phosphorylation of IκB kinase complex in response to IL-1ß stimulation, whereas treatment with a specific p-IκB kinase inhibitor attenuated MMP-3 and MMP-13 expression. Our results indicated that p21-deficient DMM mice were susceptible to alterations in OA phenotype, including enhanced osteoclast expression, macrophage infiltration, and MMP expression through IL-1ß-induced NF-κB signaling, suggesting that p21 regulation may constitute a possible therapeutic strategy for OA treatment. © 2017 American Society for Bone and Mineral Research.