Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis.

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1ß or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium.

Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry.

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

Sonography of Morton Neuromas: What Are We Really Looking At?

OBJECTIVES: To determine what accounts for the sonographic appearance of a Morton neuroma by correlating preoperative sonograms with the sonographic appearance of the resected surgical specimen, the surgical findings, and the pathologic examination. METHODS: Ten Morton neuromas that had preoperative sonograms underwent postoperative specimen sonography and histologic evaluation. The appearance and size of the neuromas were compared between the preoperative and postoperative specimen images and were compared to the surgical and pathologic appearances. RESULTS: Preoperative images showed a fibrillar echogenic nerve coursing into a heterogeneous hypoechoic mass measuring 14.3 mm in average length (range, 9.0-24.0 mm) that contained a round, mildly echogenic mass within it measuring 7.6 mm in average length (range, 4.5-12.0 mm). Surgically, the specimens showed scarred intermetatarsal bursas and tangled vessels surrounding the nerve. Specimen sonography showed echogenic focal enlargement of the nerve at the site of the neuroma, measuring 6.8 mm in average length (range, 3.5-11.0 mm). The size of the resected neuroma was smaller than the hypoechoic mass on the presurgical images (P < .001). Within the hypoechoic mass, the small echogenic focus showed no difference in size compared to the specimen (P = .40), but the shape of the echogenic specimen was fusiform, whereas the preoperative appearance was round. Histologically, the resected specimens showed sclerosis and mucoid degeneration of the nerve fascicles and fibrotic thickening of the perineurium. CONCLUSIONS: The hypoechoic heterogeneous mass that is referred to as a Morton neuroma sonographically is really a "neuroma-bursal complex" that is much larger than the actual neuroma itself.

The effect of myofibroblasts and corticosteroid injections in adhesive capsulitis.

HYPOTHESIS: Adhesive capsulitis is a condition that results in restricted glenohumeral motion. Fibroblasts have been implicated in the disease process; however, their role as a contractile element in the development of fibrosis and capsular contracture is not well understood. We hypothesized (1) that myofibroblast prevalence in capsular biopsy specimens from patients with adhesive capsulitis would be increased compared with controls and (2) that patients treated with an intra-articular injection of corticosteroid would have fewer myofibroblasts. METHODS: The study prospectively enrolled 20 consecutive patients with adhesive capsulitis scheduled for capsular release and matched controls. Tissue samples were collected from the posterior and anterior capsule for histomorphologic and immunohistologic analyses. Identical sectioning and preparation was performed in 14 additional adhesive capsulitis specimens from patients who had not received corticosteroid injections. RESULTS: Patients with adhesive capsulitis not treated with preoperative corticosteroid demonstrated more histologic evidence of fibromatosis, synovial hyperplasia, and an increase in positive staining for α-smooth muscle actin than patients who had received intra-articular injections of steroid. No specimens obtained from control patients demonstrated positive staining for α-smooth muscle actin. DISCUSSION: There was a higher prevalence of myofibroblast staining in patients with adhesive capsulitis, implicating activation of the myofibroblast in the pathophysiology of capsular contracture. Intra-articular steroid injection decreases the presence and amount of fibromatosis, vascular hyperplasia, fibrosis, and the presence of fibroblasts staining for α-smooth muscle actin. This supports the use of steroid injections to alter the disease process by decreasing the pathologic changes found in the capsular tissue.

Blood-induced arthropathy in hemophilia: mechanisms and heterogeneity.

Hemophilia A is an X-linked bleeding disorder that can be largely controlled by treatment with recombinant factor VIII. However, this treatment is only partially effective in preventing hemophilic arthropathy (HA), a debilitating degenerative joint disease that is caused by intra-articular bleeding events. The disease progression of HA has several distinct steps, beginning with hemophilic synovitis (HS), a hyperplasia of the synovial lining coupled with a neovascular response, followed by joint erosion with cartilage destruction and erosion of the underlying bone. The early stages of HA have certain features in common with arthritides such as rheumatoid arthritis (RA), whereas the later degenerative stages of HA have some similarities with osteoarthritis (OA). The main purpose of this review is to explore the similarities between HA with RA and OA and discuss how this information could potentially help understand the pathogenesis of HA and uncover new treatment opportunities.

Spontaneous intraneural hematoma of the sural nerve.

Symptomatic intraneural hemorrhage occurs rarely. It presents with pain and/or weakness in the distribution following the anatomic innervation pattern of the involved nerve. When a purely sensory nerve is affected, the symptoms can be subtle. We present a previously healthy 36-year-old female who developed an atraumatic, spontaneous intraneural hematoma of her sural nerve. Sural dysfunction was elicited from the patient's history and physical examination. The diagnosis was confirmed with magnetic resonance imaging, and surgical decompression provided successful resolution of her preoperative symptoms. To our knowledge, this entity has not been reported previously. Our case highlights the importance of having a high index of suspicion for nerve injury or compression in patients whose complaints follow a typical peripheral nerve distribution. Prior studies have shown that the formation of intraneural hematoma and associated compression of nerve fibers result in axonal degeneration, and surgical decompression decreases axonal degeneration and aids functional recovery.

Recurrent pigmented villonodular synovitis and multifocal giant cell tumor of the tendon sheath: case report.

Intra- and extra-articular giant cell tumor of tendon sheath (GCTTS) and pigmented villonodular synovitis (PVNS) are histologically similar, usually benign tumors that can be characterized by synovial involvement (GCTTS) or overgrowth (PVNS). These tumors are most often found in the knee and digits of the hand. Although recurrence is a common feature of both conditions, multifocal lesions are rare. We present an unusual case of multifocal, recurrent, bilateral GCTTS/PVNS involving both upper and lower extremities. Recurrent right ankle and right index finger masses, in addition to masses on the right small finger and left thumb, were excised over a 14-year period.

Characteristics of glomus tumors in the hand not diagnosed on magnetic resonance imaging.

PURPOSE: To determine whether the diagnosis of hand glomus tumors by magnetic resonance imaging (MRI) is associated with tumor size, tumor pathology, tumor location, and/or clinical suspicion. METHODS: We reviewed our pathology database for patients with hand glomus tumors diagnosed between 2006 and 2013 and included those patients who had preoperative MRI at our institution. We excluded patients with recurrent and persistent tumors. Magnetic resonance imaging reports were reviewed for clinical history, tumor location, and associated bone erosion. Pathology reports were reviewed for diagnosis and tumor size. We classified MRI studies as positive (glomus tumor diagnosis), negative (no mention of glomus tumor as possible diagnosis), or indeterminate (glomus tumor mentioned as possible differential diagnosis). Fisher exact test was used to compare positive studies and those that were nondiagnostic (ie, either negative or indeterminate). RESULTS: Of the 46 patients who had pathologically confirmed hand glomus tumors, 38 had preoperative MRI studies. A total of 24 MRI studies were positive, 5 were indeterminate, and 7 were negative. Five patients had atypical pathology, 1 had a multifocal tumor, and 2 had extra-digital hand glomus tumors. Failure to diagnose glomus tumors on MRI was associated with atypical pathology, atypical location (ie, not located in the subungual region), absence of bone erosion, and lack of clinical suspicion. Tumor size was not associated with MRI diagnosis. CONCLUSIONS: In this series of 36 hand glomus tumors, one-third of MRI studies were nondiagnostic. Occurrence of nondiagnostic MRIs was more likely when glomus tumors were pathologically and/or anatomically atypical, without bone erosion, and with no or unrelated clinical history provided. These findings highlight the continued importance of clinical suspicion in glomus tumor diagnosis. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

The anatomy and histology of the bicipital tunnel of the shoulder.

BACKGROUND: The bicipital tunnel is the extra-articular, fibro-osseous structure that encloses the long head of the biceps tendon. METHODS: Twelve cadaveric shoulder specimens underwent in situ casting of the bicipital tunnel with methyl methacrylate cement to demonstrate structural competence (n = 6) and en bloc harvest with gross and histologic evaluation (n = 6). The percentage of empty tunnel was calculated histologically by subtracting the proportion of cross-sectional area of the long head of the biceps tendon from that of the bicipital tunnel for each zone. RESULTS: Cement casting demonstrated that the bicipital tunnel was a closed space. Zone 1 extended from the articular margin to the distal margin of the subscapularis tendon. Zone 2 extended from the distal margin of the subscapularis tendon to the proximal margin of the pectoralis major tendon. Zone 3 was the subpectoral region. Zones 1 and 2 were both enclosed by a dense connective tissue sheath and demonstrated the presence of synovium. Zone 3 had significantly greater percentage of empty tunnel than zones 1 and 2 did (P < .01). CONCLUSION: The bicipital tunnel is a closed space with 3 distinct zones. Zones 1 and 2 have similar features, including the presence of synovium, but differ from zone 3. A significant bottleneck occurs between zone 2 and zone 3, most likely at the proximal margin of the pectoralis major tendon. The bicipital tunnel is a closed space where space-occupying lesions may produce a bicipital tunnel syndrome. Careful consideration should be given to surgical techniques that decompress both zones 1 and 2 of the bicipital tunnel.

An atraumatic case of extensive Achilles tendon ossification.

BACKGROUND: Ossification of the Achilles tendon is rare with most cases of ossification or calcification consisting of small, focal lesions. This pathology is usually predisposed by surgery, trauma, or other factors. CASE DESCRIPTION: A case of extensive Achilles ossification and calcification, without prior surgery or trauma, is reported. Following removal of one of the largest ossific masses reported in the literature, measuring 11.0cm×2.5cm×2.0cm with additional 6.5cm calcifications, surgical reconstruction was required. PURPOSE AND CLINICAL RELEVANCE: The objective of this report was to describe an unusual case of Achilles tendon ossification and calcification that occurred without the presence of predisposing factors. When a large gap is present after removal of the ossification, direct repair may be impossible and V-Y lengthening plus flexor hallucis longus (FHL) transfer is a viable option for pain relief and return to function.

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene-related peptide (CGRP+). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP+ dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP+ pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.

Cellular response to prosthetic wear debris differs in patients with and without rheumatoid arthritis.

OBJECTIVE: To examine whether patients with rheumatoid arthritis (RA) demonstrate patterns of prosthetic wear or cellular responses to implant wear debris different from those demonstrated by patients without inflammatory joint disease. METHODS: Thirty-eight patients who had undergone a primary revision of a total elbow arthroplasty for aseptic loosening between 1996 and 2008 were identified. Twenty-five of these patients had RA, and 13 did not have inflammatory arthritis. Clinical data, gross wear patterns of the removed prostheses, and histopathologic analyses of peri-implant tissue were compared between the patients with RA and those without RA. RESULTS: Evaluation of the retrieved prostheses showed that conformational change of the humeral polyethylene bushing was associated with the generation of polyethylene and metal particles. The amount and type of wear debris in periprosthetic tissues were similar in patients with and those without RA. Patients with RA who were not receiving anti-tumor necrosis factor (anti-TNF) therapy exhibited a histologic pattern of interstitial and sheet-like lymphocytic infiltrates associated with a high plasma cell composition, which was different from the predominantly perivascular infiltrates with few plasma cells seen in non-RA patients (P = 0.04). Patients with RA who were receiving anti-TNF therapy showed a mixed perivascular and interstitial pattern of infiltrates with variable cell composition. CONCLUSION: Patients with RA exhibited a distinct cellular response to implant wear debris compared with patients without RA. This reaction was unrelated to differences in the type or amount of wear debris and was mitigated by anti-TNF therapy. These results suggest an intrinsic alteration in immunoregulation in RA and have implications for potential immunologic treatment of osteolysis in these patients.

Aseptic lymphocyte dominated vasculitis-associated lesion resulting from trunnion corrosion in a cobalt-chrome unipolar hemiarthroplasty.

Most of the published descriptions of adverse soft tissue reactions that have been reported in the context of a metal-on-metal articulation have been in cases of total hip arthroplasty or resurfacing arthroplasty. Recently, several case reports have been published describing aseptic lymphocyte dominated vasculitis-associated lesions (ALVAL) in metal-on-polyethylene. To our knowledge, there has not been a description of a similar, aggressive reaction secondary to metal debris from the head-neck junction of a unipolar hemiarthroplasty component. In this case report, we describe a patient with a catastrophic failure of a unipolar hip hemiarthroplasty, secondary to aggressive osteolysis and an inflammatory mediated immunological reaction to metal debris.

Computer Vision Analysis of Rheumatoid Arthritis Synovium Reveals Lymphocytic Inflammation Is Associated With Immunoglobulin Skewing in Blood.

OBJECTIVE: We sought to develop computer vision methods to quantify aggregates of cells in synovial tissue and compare these with clinical and gene expression parameters. METHODS: We assembled a computer vision pipeline to quantify five features encompassing synovial cell density and aggregates and compared these with pathologist scores, disease classification, autoantibody status, and RNA expression in a cohort of 156 patients with rheumatoid arthritis (RA) and 149 patients with osteoarthritis (OA). RESULTS: All five features were associated with pathologist scores of synovial lymphocytic inflammation (P < 0.0001). Three features that related to the cells per unit of tissue were significantly increased in patients with both seronegative and seropositive RA compared with those with OA; on the other hand, aggregate features (number and diameter) were significantly increased in seropositive, but not seronegative, RA compared with OA. Aggregate diameter was associated with the gene expression of immunoglobulin heavy-chain genes in the synovial tissue. Compared with blood, synovial immunoglobulin isotypes were skewed from IGHM and IGHD to IGHG3 and IGHG1. Further, patients with RA with high levels of lymphocytic infiltrates in the synovium demonstrated parallel skewing in their blood with a relative decrease in IGHGM (P < 0.002) and IGHD (P < 0.03) and an increase in class-switched immunoglobulin genes IGHG3 (P < 0.03) and IGHG1 (P < 0.002). CONCLUSION: High-resolution automated identification and quantification of synovial immune cell aggregates uncovered skewing in the synovium from naïve IGHD and IGHM to memory IGHG3 and IGHG1 and revealed that this process is reflected in the blood of patients with high inflammatory synovium.

Machine learning identification of thresholds to discriminate osteoarthritis and rheumatoid arthritis synovial inflammation.

BACKGROUND: We sought to identify features that distinguish osteoarthritis (OA) and rheumatoid arthritis (RA) hematoxylin and eosin (H&E)-stained synovial tissue samples. METHODS: We compared fourteen pathologist-scored histology features and computer vision-quantified cell density (147 OA and 60 RA patients) in H&E-stained synovial tissue samples from total knee replacement (TKR) explants. A random forest model was trained using disease state (OA vs RA) as a classifier and histology features and/or computer vision-quantified cell density as inputs. RESULTS: Synovium from OA patients had increased mast cells and fibrosis (p < 0.001), while synovium from RA patients exhibited increased lymphocytic inflammation, lining hyperplasia, neutrophils, detritus, plasma cells, binucleate plasma cells, sub-lining giant cells, fibrin (all p < 0.001), Russell bodies (p = 0.019), and synovial lining giant cells (p = 0.003). Fourteen pathologist-scored features allowed for discrimination between OA and RA, producing a micro-averaged area under the receiver operating curve (micro-AUC) of 0.85±0.06. This discriminatory ability was comparable to that of computer vision cell density alone (micro-AUC = 0.87±0.04). Combining the pathologist scores with the cell density metric improved the discriminatory power of the model (micro-AUC = 0.92±0.06). The optimal cell density threshold to distinguish OA from RA synovium was 3400 cells/mm2, which yielded a sensitivity of 0.82 and specificity of 0.82. CONCLUSIONS: H&E-stained images of TKR explant synovium can be correctly classified as OA or RA in 82% of samples. Cell density greater than 3400 cells/mm2 and the presence of mast cells and fibrosis are the most important features for making this distinction.

Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.

Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38hiCD127- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.

Machine Learning Reveals Synovial Fibroblast Genes Associated with Pain Affect Sensory Nerve Growth in Rheumatoid Arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We identified a module of 815 genes associated with pain, using a novel machine learning approach, Graph-based Gene expression Module Identification (GbGMI), in samples from patients with longstanding RA, but limited synovial inflammation at arthroplasty, and validated this finding in an independent cohort of synovial biopsy samples from early, untreated RA patients. Single-cell RNA-seq analyses indicated these genes were most robustly expressed by lining layer fibroblasts and receptor-ligand interaction analysis predicted robust lining layer fibroblast crosstalk with pain sensitive CGRP+ dorsal root ganglion sensory neurons. Netrin-4, which is abundantly expressed by lining fibroblasts and associated with pain, significantly increased the branching of pain-sensitive CGRP+ neurons in vitro . We conclude GbGMI is a useful method for identifying a module of genes that associate with a clinical feature of interest. Using this approach, we find that Netrin-4 is produced by synovial fibroblasts in the absence of inflammation and can enhance the outgrowth of CGRP+ pain sensitive nerve fibers. One Sentence Summary: Machine Learning reveals synovial fibroblast genes related to pain affect sensory nerve growth in Rheumatoid Arthritis addresses unmet clinical need.

High- and low-dose OPG-Fc cause osteopetrosis-like changes in infant mice.

BACKGROUND: Receptor activator of nuclear factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin-immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wild-type controls (+/+). METHODS: Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b, TRACP-5b) until 25 wk of age. RESULTS: Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment. CONCLUSION: Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK-immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.

Synovial inflammation in patients undergoing arthroscopic meniscectomy: molecular characterization and relationship to symptoms.

OBJECTIVE: Traumatic and degenerative meniscal tears have different anatomic features and different proposed etiologies, yet both are associated with the development or progression of osteoarthritis (OA). In established OA, synovitis is associated with pain and progression, but a relationship between synovitis and symptoms in isolated meniscal disease has not been reported. Accordingly, we sought to characterize synovial pathology in patients with traumatic meniscal injuries and determine the relationships between inflammation, meniscal and cartilage pathology, and symptoms. METHODS: Thirty-three patients without evidence of OA who were undergoing arthroscopic meniscectomy for meniscal injuries were recruited. Pain and function were assessed preoperatively; meniscal and cartilage abnormalities were documented at the time of surgery. Inflammation in synovial biopsy specimens was scored, and associations between inflammation and clinical outcomes were determined. Microarray analysis of synovial tissue was performed, and gene expression patterns in patients with and those without inflammation were compared. RESULTS: Synovial inflammation was present in 43% of the patients and was associated with worse preoperative pain and function scores, independent of age, sex, or cartilage pathology. Microarray analysis and real-time polymerase chain reaction revealed a chemokine signature in synovial biopsy specimens with increased inflammation scores. CONCLUSION: Our findings indicate that in patients with traumatic meniscal injury undergoing arthroscopic meniscectomy without radiographic evidence of OA, synovial inflammation occurs frequently and is associated with increased pain and dysfunction. Synovia with increased inflammation scores exhibit a unique chemokine signature. Chemokines may contribute to the development of synovial inflammation in patients with meniscal pathology; they also represent potential therapeutic targets for reducing inflammatory symptoms.