[Fibrocartilaginous lipoma: a clinicopathological analysis of six cases].

Objective: To investigate the clinicopathological characteristics, immunophenotype, molecular genetics and differential diagnoses of fibrocartilaginous lipomas which consist of adipose tissue, fibrocartilage and fibrous elements. Methods: The clinicopathological features, immunohistochemical profiles and molecular profiles in six cases of fibrocartilaginous lipomas diagnosed at Foshan Traditional Chinese Medicine Hospital, Fudan University Shanghai Cancer Center, the Fifth Affiliated Hospital of Zhengzhou University and the Fourth Affiliated Hospital of Harbin Medical University from January 2017 to February 2022 were included. The follow-up information, diagnosis and differential diagnoses were evaluated. Results: There were three males and three females with a median age of 53 years (range 36-69 years) at presentation. Tumors were located in the extremities, the head and neck region and trunk; and presented as painless masses that were located in the subcutaneous tissue or deep soft tissue. Grossly, three cases were well defined with thin capsule, one case was well circumscribed without capsule, two cases were surrounded by some skeletal muscle. The tumors were composed of fatty tissue with intermingled gray-white area. The tumors ranged from 1.50-5.50 cm (mean 2.92 cm). Microscopically, the hallmark of these lesions was the complex admixture of mature adipocytes, fibrocartilage and fibrous element in varying proportions; the fibrocartilage arranged in a nodular, sheet pattern with some adipocytes inside. Tumor cells had a bland appearance without mitotic activity. Immunohistochemical analysis using antibodies to SMA, desmin, S-100, SOX9, HMGA2, RB1, CD34, adipopholin was performed in six cases; the fibrocartilage was positive for S-100 and SOX9, adipocytes were positive for S-100, adipopholin and HMGA2; CD34 was expressed in the fibroblastic cells, while desmin and SMA were negative. Loss of nuclear RB1 expression was not observed. Other genetic abnormalities had not been found yet in four cases. Follow-up information was available in six cases; there was no recurrence in five, and one patient only underwent biopsy of the mass. Conclusions: Fibrocartilaginous lipoma is a benign lipomatous tumor with mature adipocytes, fibrocartilage and fibrous elements. By immunohistochemistry, they show the expression of fat and cartilage markers. No specific molecular genetics changes have been identified so far. Familiarity with its clinicopathological features helps the distinction from its morphologic mimics.

Mineral tessellation in mouse enthesis fibrocartilage, Achilles tendon, and Hyp calcifying enthesopathy: A shared 3D mineralization pattern.

The hallmark of enthesis architecture is the 3D compositional and structural gradient encompassing four tissue zones - tendon/ligament, uncalcified fibrocartilage, calcified fibrocartilage and bone. This functional gradient accommodates the large stiffness differential between calcified bone and uncalcified tendon/ligament. Here we analyze in 3D the organization of the mouse Achilles enthesis and mineralizing Achilles tendon in comparison to lamellar bone. We use correlative, multiscale high-resolution volume imaging methods including µCT with submicrometer resolution and FIB-SEM tomography (both with deep learning-based image segmentation), and TEM and SEM imaging, to describe ultrastructural features of physiologic, age-related and aberrant mineral patterning. We applied these approaches to murine wildtype (WT) Achilles enthesis tissues to describe in normal calcifying fibrocartilage a crossfibrillar mineral tessellation pattern similar to that observed in lamellar bone, but with greater variance in mineral tesselle morphology and size. We also examined Achilles enthesis structure in Hyp mice, a murine model for the inherited osteomalacic disease X-linked hypophosphatemia (XLH) with calcifying enthesopathy. In Achilles enthesis fibrocartilage of Hyp mice, we show defective crossfibrillar mineral tessellation similar to that which occurs in Hyp lamellar bone. At the cellular level in fibrocartilage, unlike in bone where enlarged osteocyte mineral lacunae are found as peri-osteocytic lesions, mineral lacunar volumes for fibrochondrocytes did not differ between WT and Hyp mice. While both WT and Hyp aged mice demonstrate Achilles tendon midsubstance ectopic mineralization, a consistently defective mineralization pattern was observed in Hyp mice. Strong immunostaining for osteopontin was observed at all mineralization sites examined in both WT and Hyp mice. Taken together, this new 3D ultrastructural information describes details of common mineralization trajectories for enthesis, tendon and bone, which in Hyp/XLH are defective.

Regulatory role of human fibrocartilage stem cells in condyle osteochondroma.

OBJECTIVE: Osteochondroma is a common benign skeletal disorder for which different molecular and histological features of long bones have been reported. We investigated cell-of-origin and molecular mechanisms of a rare condylar osteochondroma (CO). METHODS: Human fibrocartilage stem cells (hFCSCs) isolated from CO and normal condyle tissue were used for RNA sequencing, real-time PCR, Western Blotting, immunohistology, flowcytometry, as well as for chondrogenic differentiation, proliferation, and apoptosis detection assays. RESULTS: HFCSCs were fewer in number with weaker proliferative capacity and higher apoptosis ratio in the CO group. During the chondrogenic inducing process, hFCSCs from CO were prone to form more mature and hypertrophic cartilage. The result of RNA sequencing of hFCSCs from CO and normal condyle revealed a correlation between the PI3K/AKT signalling pathway and CO. Activated PI3K/AKT signalling might lead to functional changes in hFCSCs by enhancing cell apoptosis in the developmental process of CO. Increased expression of BCL2-like protein 11 (BIM) in CO tissue also supports this conclusion. Furthermore, the activation of the PI3K/AKT pathway in TMJ of mice induced histological disorder and increased apoptosis in condylar cartilage. CONCLUSION: We conclude that the activation of PI3K/AKT signalling in hFCSCs of CO suggests a new hypothesis for the cell-of-origin of human CO and another possible target to treat it.

Editorial Commentary: The Measurement of the Alpha Angle in Femoroacetabular Impingement Syndrome With a 45° Dunn-View Radiograph Predicts the Cartilage Damage on the Acetabular Side of the Hip Joint-Is It as Simple as That?

In recent years, femoroacetabular impingement syndrome (FAIS) has developed itself into a well-known pathology throughout the orthopaedic community worldwide. The more we learned, the more sophisticated it became: In the beginning, we measured the femoral head-neck offset; then, the alpha angle was found to be a useful measurement in detecting FAIS. We learned to perform these measurements with, for example, the 45° Dunn view. The alpha angle, but not the femoral head-neck offset, measured as described, predicts not only the acetabular cartilage damage resulting from FAIS but also the correlation between the degree of the alpha angle and the severity of the cartilage damage within the acetabular labrum articular disruption and Outerbridge classifications. The femoral head-neck offset cannot provide us with this information, but it is the first sign we all look at before taking any measurements on radiographs or magnetic resonance imaging scans if a cam morphology could be present. It is paramount to understand the underlying problems of the individual hip and distinguish instability (dysplasia) from FAIS and also to evaluate femoral torsional abnormalities to perform the appropriate treatment using magnetic resonance imaging and computed tomography scans if necessary. The alpha angle quantifies the severity of the pathology and predicts the possible cartilage damage in FAIS patients, but in our opinion, we cannot neglect the femoral head-neck offset, because it is often the first radiologic sign of FAIS that most of us realize on a radiograph. Therefore, both signs have their place in detecting and treating FAIS.

Regulating Fibrocartilage Stem Cells via TNF-α/Nf-κB in TMJ Osteoarthritis.

In this study, we investigate harnessing fibrocartilage stem cell (FCSC) capacities by regulating tumor necrosis factor α (TNF-α) signaling for cartilage repair in temporomandibular joint osteoarthritis (TMJOA). Stem cell specifics for FCSCs were characterized in the presence of TNF-α. Etanercept as a TNF-α inhibitor and BAY 11-7082 as an Nf-κB inhibitor were used to study TNF-α regulation of FCSCs. Lineage tracing was performed in Gli1-CreERT+;Tmfl/fl mice when etanercept (1 mg/kg, every 3 d) or isometric vehicle was subcutaneously injected to trace specific changes in FCSCs. Surgically induced TMJOA Sprague-Dawley rats were generated with BAY 11-7082 (5 mg/kg, every 3 d) or vehicle subcutaneous injection to investigate the functional role of TNF-α/Nf-κB in TMJOA. Anterior disc displacement (ADD) rabbits were used to analyze the therapeutic effect of etanercept as a TMJOA intra-articular treatment with etanercept (0.02 mg in 100 µL, every 2 wk) or isometric vehicle. In vitro, TNF-α inhibited proliferation of FCSCs and increased FCSC apoptosis. TNF-α activation interfered with osteogenic and chondrogenic differentiation of FCSCs, while etanercept could partially recover FCSC specificity from TNF-α. FCSC lineage tracing in Gli1-CreERT+;Tmfl/fl mice showed that the chondrogenic capacity of Gli1+ cell lineage was markedly suppressed in osteoarthritis cartilage, the phenotype of which could be significantly rescued by etanercept. Specifically blocking the Nf-κB pathway could significantly weaken the regulatory effect of TNF-α on FCSC specificity in vitro and in TMJOA rats in vivo. Finally, intra-articular etanercept treatment efficiently rescued TMJ cartilage degeneration and growth retardation in ADD rabbits. Inhibition of TNF-α signaling reduced Nf-κB transcripts and recovered FCSC specificities. In vivo, etanercept treatment effectively rescued the osteoarthritis phenotype in TMJOA mice and ADD rabbits. These data suggest a novel therapeutic mechanism whereby TNF-α/Nf-κB inhibition promotes FCSC chondrogenic capacity for cartilage transformation in TMJOA.

Single-Cell Integration Analysis of Heterotopic Ossification and Fibrocartilage Developmental Lineage: Endoplasmic Reticulum Stress Effector Xbp1 Transcriptionally Regulates the Notch Signaling Pathway to Mediate Fibrocartilage Differentiation.

INTRODUCTION: Regeneration of fibrochondrocytes is essential for the healing of the tendon-bone interface (TBI), which is similar to the formation of neurogenic heterotopic ossification (HO). Through single-cell integrative analysis, this study explored the homogeneity of HO cells and fibrochondrocytes. METHODS: This study integrated six datasets, namely, GSE94683, GSE144306, GSE168153, GSE138515, GSE102929, and GSE110993. The differentiation trajectory and key transcription factors (TFs) for HO occurrence were systematically analyzed by integrating single-cell RNA (scRNA) sequencing, bulk RNA sequencing, and assay of transposase accessible chromatin seq. The differential expression and enrichment pathways of TFs in heterotopically ossified tissues were identified. RESULTS: HO that mimicked pathological cells was classified into HO1 and HO2 cell subsets. Results of the pseudo-temporal sequence analysis suggested that HO2 is a differentiated precursor cell of HO1. The analysis of integrated scRNA data revealed that ectopically ossified cells have similar transcriptional characteristics to cells in the fibrocartilaginous zone of tendons. The modified SCENIC method was used to identify specific transcriptional regulators associated with ectopic ossification. Xbp1 was defined as a common key transcriptional regulator of ectopically ossified tissues and the fibrocartilaginous zone of tendons. Subsequently, the CellPhoneDB database was completed for the cellular ligand-receptor analysis. With further pathway screening, this study is the first to propose that Xbp1 may upregulate the Notch signaling pathway through Jag1 transcription. Twenty-four microRNAs were screened and were found to be potentially associated with upregulation of XBP1 expression after acute ischemic stroke. CONCLUSION: A systematic analysis of the differentiation landscape and cellular homogeneity facilitated a molecular understanding of the phenotypic similarities between cells in the fibrocartilaginous region of tendon and HO cells. Furthermore, by identifying Xbp1 as a hub regulator and by conducting a ligand-receptor analysis, we propose a potential Xbp1/Jag1/Notch signaling pathway.

BMP7 reduces the fibrocartilage chondrocyte phenotype.

The fibrocartilage chondrocyte phenotype has been recognized to attribute to osteoarthritis (OA) development. These chondrocytes express genes related to unfavorable OA outcomes, emphasizing its importance in OA pathology. BMP7 is being explored as a potential disease-modifying molecule and attenuates the chondrocyte hypertrophic phenotype. On the other hand, BMP7 has been demonstrated to relieve organ fibrosis by counteracting the pro-fibrotic TGFß-Smad3-PAI1 axis and increasing MMP2-mediated Collagen type I turnover. Whether BMP7 has anti-fibrotic properties in chondrocytes is unknown. Human OA articular chondrocytes (HACs) were isolated from end-stage OA femoral cartilage (total knee arthroplasty; n = 18 individual donors). SW1353 cells and OA HACs were exposed to 1 nM BMP7 for 24 h, after which gene expression of fibrosis-related genes and fibrosis-mediating factors was determined by RT-qPCR. In SW1353, Collagen type I protein levels were determined by immunocytochemistry and western blotting. PAI1 and MMP2 protein levels and activity were measured with an ELISA and activity assays, respectively. MMP2 activity was inhibited with the selective MMP-2 inhibitor OA-Hy. SMAD3 activity was determined by a (CAGA)12-reporter assay, and pSMAD2 levels by western blotting. Following BMP7 exposure, the expression of fibrosis-related genes was reduced in SW1353 cells and OA HACs. BMP7 reduced Collagen type I protein levels in SW1353 cells. Gene expression of MMP2 was increased in SW1353 cells following BMP7 treatment. BMP7 reduced PAI1 protein levels and -activity, while MMP2 protein levels and -activity were increased by BMP7. BMP7-dependent inhibition of Collagen type I protein levels in SW1353 cells was abrogated when MMP2 activity was inhibited. Finally, BMP7 reduced pSMAD2 levels determined by western blotting and reduced SMAD3 transcriptional activity as demonstrated by decreased (CAGA)12 luciferase reporter activity. Our data demonstrate that short-term exposure to BMP7 decreases the fibrocartilage chondrocyte phenotype. The BMP7-dependent reduction of Collagen type I protein expression seems MMP2-dependent and inhibition of Smad2/3-PAI1 activity was identified as a potential pathway via which BMP7 exerts its anti-fibrotic action. This indicates that in chondrocytes BMP7 may have a double mode-of-action by targeting both the hypertrophic as well as the fibrotic chondrocyte phenotype, potentially adding to the clinical relevance of using BMP7 as an OA disease-modifying molecule.

Gene expression profiling of primary fibrochondrocyte cultures in traumatic and degenerative meniscus lesions.

PURPOSE: This study aimed to investigate how fibroblastic and chondrocytic properties of human meniscal fibrochondrocytes are affected in culture conditions according to the type of meniscal pathology and localization, and to provide basic information for tissue-engineering studies. METHODS: Primary fibrochondrocyte cultures were prepared from meniscus samples of patients who had either traumatic tear or degeneration due to osteoarthritis. Cultures were compared in terms of mRNA expression levels of COL1A1, COL2A1, COMP1, HIF1A, HIF2A, and SOX9 and secreted total collagen and sulfated sGAG levels according to the type of meniscal pathology, anatomical localization, and the number of subcultures. RESULTS: mRNA expression levels of COL1A1, COMP1, HIF1A, HIF2A, and SOX9 were found to be increased in subsequent subcultures in all specimens. COL1A1 mRNA expression levels of both lateral and medial menisci of patients with traumatic tear were significantly higher than in patients with degenerative pathology, indicating a more fibroblastic character. P1 subculture of lateral and P3 or further subculture of medial meniscus showed more fibroblastic characteristics in patients with degenerative pathology. Furthermore, in patients with degenerative pathology, the subcultures of the lateral meniscus (especially on the inner part) presented more chondrocytic characteristics than did those of medial meniscus. CONCLUSIONS: The mRNA expression levels of the cultures showed significant differences according to the anatomical localization and pathology of the meniscus, indicating distinct chondrocytic and fibroblastic features. This fundamental knowledge would help researchers to choose more efficient cell sources for cell-seeding of a meniscus scaffold, and to generate a construct resembling the original meniscus tissue.

An evaluation of the relationship between the degree of entheseal changes and the severity of osteodegenerative processes at fibrocartilaginous entheses.

An enthesis refers to the interface at which a tendon or a ligament integrates into the periosteum. Its morphology can be influenced by intrinsic factors such as sex, age, and extrinsic factors such as levels of activity, which will in turn impact on bone remodeling and lead to morphological changes. In bioarcheology, entheseal changes have had a long tradition of being used for the reconstruction of past activities. The literature has shown that in some cases of osteoarthritis, entheseal changes are associated with osteoarthritic manifestations. This work aims to evaluate the relationship between the degree of entheseal changes and the severity of osteodegenerative processes. The studied materials consisted of 30 humeri and 30 femora from the osteological collection at St George's University of London. Intensities of both entheseal changes and osteodegenerative processes were macroscopically assessed and scored. The difference in scores of entheseal changes between osteoarthritic groups and nonosteoarthritic groups is statistically significant at a confidence level of 95% (α = .05) for both the humeri and femora. Results show a positive correlation between the degree of entheseal changes and the severity of osteodegenerative processes in the femora, suggesting that enthesis may play a role in osteoarthritis. Findings from this work supports the proposed hypothesis that the degree of entheseal changes and the severity of osteoarthritic manifestation are related. This work contributes to current knowledge that osteoarthritis is a disease involving the whole joint; the enthesis could potentially be a target for the diagnosis of osteoarthritis.

A entese refere-se à interface por meio da qual um tendão ou um ligamento se integra ao periósteo. Sua morfologia pode ser influenciada por fatores intrínsecos como sexo, idade e fatores extrinsecos como niveis de atividade, que por sua vez impactam na remodelacção óssea e levam à alterações morfológicas. Em bioarqueologia, o uso das alterações das enteses tem uma longa tradição de reconstruir atividades passadas. A literatura evidencia que, em alguns casos de osteoartrite, as alterações das enteses estão associadas às manifestações osteoartríticas. Esta pesquisa tem como objetivo avaliar a relação entre o grau de alterações das enteses e a severidade de processo osteo-patológicos. O material estudado consiste em 30 úmeros e 30 fêmures provenientes da coleção osteologica da St George's University of London. A intensidade de ambos, alteraçoes das enteses e processo osteodegenerativo foram avaliados e classificados macroscopicamente. A diferença na intensidade das alterações das enteses entre os grupos com e sem osteoartrite é estatisiticamente significativa à um nivel de confiança de 95% (α = .05) para ambos, úmeros e fêmures. Os resultados mostram uma correlação positiva entre o grau de alteração das enteses e a severidade dos processos osteodegenerativos nos fêmures, sugerindo que as enteses podem desempenhar um papel na fisiopatologia da osteoartrite. Os achados dessa pesquisa apoiam a hipótese proposta de que o grau de alteração das enteses e a severidade das manifestações da osteoartrites estão relacionados. Esta investigação contribui para o conhecimento atual de que a osteoartrite é uma patologia que envolve toda a articulação e que as enteses podem ser potencialmente um alvo para o diagnóstico da ostaoartrite.

Cartilage calcification is associated with histological degeneration of the knee joint: a highly prevalent, age-independent systemic process.

OBJECTIVES: To investigate if cartilage calcification (CC) is a systemic process, the purpose of this study was to determine the prevalence and the amount of meniscal/hyaline CC of the knee joint in the general population by high-resolution imaging (DCR) and to evaluate the association between CC with cartilage degeneration and age. METHODS: Cross-sectional DCR-study of 180 knee joints of 90 donors (42 female/48 male, mean age 62.3y). Histological hyaline (OARSI) and meniscal (Krenn) cartilage degeneration was determined of all knees. RESULTS: CC was observed in 100% of the donors (bilaterally in 98%), hyaline cartilage calcification (HCC) in 92% and meniscal calcification (MC) in 100%. CC was detected in more than three out of six distinct cartilage areas in 84.4% of all knees. The mean amount of CC correlated between both sides of donors, the different analyzed areas of the knee joint and between the various types of cartilage structures. There was more calcification in meniscal than in hyaline cartilage (factor 5.3) and in the medial than the lateral compartment (factor 1.2). HCC/MC were already detectable with only mild cartilage lesions and the amount correlated with histological cartilage degeneration, but not with age. CONCLUSIONS: The present study provides evidence that meniscal and hyaline CC occurs in a pattern that is compatible with CC being a systemically driven process and that meniscal fibrocartilage is more prone to calcification than hyaline cartilage. Furthermore, the age-independent association between the amount of CC and the grade of degeneration in both hyaline and meniscal cartilage, suggests that CC is an obligatory early event in initiating cartilage degeneration.

Congenital soft tissue stenosis of the external auditory canal with canal cholesteatoma: Case report and literature review.

Congenital external auditory canal stenosis (EACS) is a spectrum of abnormalities affecting the external and middle ear. We report a 6 year-old patient with EACS affecting the lateral fibrocartilaginous canal that was successfully repaired. This patient highlights a variant of EACS characterized by lateral soft tissue narrowing with normal osseous development. Most previous studies of CAA have described severe forms associated with complete atresia, bony stenosis, and middle ear malformations. Stenosis affecting only the fibrocartilaginous canal is a milder form resulting from premature arrest of the canalization process during embryologic development, and may predispose to cholesteatoma formation.

Effect of suprascapular nerve injury on rotator cuff enthesis.

BACKGROUND: Numerous reports have shown that retracted rotator cuff tears may cause suprascapular nerve injury, and nerve injury causes atrophy and fat accumulation in the rotator cuff muscles. However, the effect of suprascapular nerve injury on rotator cuff enthesis has not been directly defined. This study aimed to investigate the effect of suprascapular nerve injury on rotator cuff enthesis. METHODS: Twenty-four Wistar albino rats underwent bilateral transection of the suprascapular nerve. Additional 6 rats were used as the sham group. Bilateral supraspinatus and infraspinatus entheses were examined after 1, 4, 8, and 12 weeks of nerve transection. Histomorphometric analyses were performed for each zone of enthesis. RESULTS: Compared with normal enthesis, significant and consistent decrease in cellularity were observed in the tendon and bone at all time points (P < .001). Collagen bundle diameter in the tendon also decreased in a similar manner (P < .001). Apart from the tendon and bone zones, fibrocartilage and calcified fibrocartilage zones showed similar response, and significant decrease in cellularity was observed 8 weeks after nerve transection (P < .001). CONCLUSION: This study identifies suprascapular nerve injury as an underlying mechanism leading to compromise of the rotator cuff enthesis structure. Suprascapular nerve injury may be considered as an etiologic factor for the impaired healing after repair of a massive tear.

Morphology of Spring Ligament Fibrocartilage Complex Lesions.

BACKGROUND: The spring ligament fibrocartilage complex (SLFC) is an important static foot stabilizer comprising the superomedial ligament (SML) and the inferior ligament, with anatomical variations (third ligament). The aim of this study was to describe the patterns of the lesions found during SLFC surgery, to allow direct comparison between the results with various surgical techniques. METHODS: Fourteen consecutive patients with SLFC lesions were analyzed during surgical treatment. The mean patient age was 37.3 years, and the mean time from injury was 6.9 months. Intraoperative assessments and anatomical descriptions of the lesions were collected. RESULTS: Three types of lesion were found. In 13 of 14 cases, only the superomedial ligament was involved: five superomedial ligament distentions and eight superomedial ligament ruptures. In one case, total SLFC (superomedial and inferior ligaments) rupture was observed. CONCLUSIONS: The first classification of SLFC lesions is presented, which is simple, consistent, and based on anatomical description.

The Histology of a Healed Superior Capsular Reconstruction Dermal Allograft: A Case Report.

Acellular human dermal allograft commonly is used in the surgical treatment of complex rotator cuff tears, but little information is known about the biological fate of these grafts in human subjects. In this case report, the authors describe a patient who presented with a radiographically healed acellular human dermal allograft superior capsular reconstruction but had humeral head avascular necrosis. The healed superior capsular reconstruction, including graft-bone interfaces, was explanted after 7 months and sent for histologic analysis. A successful biological reconstruction of the superior capsule was found. The graft demonstrated gross and microscopic incorporation with the host, including a tendon-like structure, aligned collagen fibers, fibroblast-like cells, and no clear graft-host distinction. Cellular infiltration ranged from 5% to 14% (central graft) to 65% to 92% (sutured attachment points). Neovascularization and active graft remodeling were confirmed histologically. LEVEL OF EVIDENCE: V, case report.

Fetal articular cartilage regeneration versus adult fibrocartilaginous repair: secretome proteomics unravels molecular mechanisms in an ovine model.

Osteoarthritis (OA), a degenerative joint disease characterized by progressive cartilage degeneration, is one of the leading causes of disability worldwide owing to the limited regenerative capacity of adult articular cartilage. Currently, there are no disease-modifying pharmacological or surgical therapies for OA. Fetal mammals, in contrast to adults, are capable of regenerating injured cartilage in the first two trimesters of gestation. A deeper understanding of the properties intrinsic to the response of fetal tissue to injury would allow us to modulate the way in which adult tissue responds to injury. In this study, we employed secretome proteomics to compare fetal and adult protein regulation in response to cartilage injury using an ovine cartilage defect model. The most relevant events comprised proteins associated with the immune response and inflammation, proteins specific for cartilage tissue and cartilage development, and proteins involved in cell growth and proliferation. Alarmins S100A8, S100A9 and S100A12 and coiled-coil domain containing 88A (CCDC88A), which are associated with inflammatory processes, were found to be significantly upregulated following injury in adult, but not in fetal animals. By contrast, cartilage-specific proteins like proteoglycan 4 were upregulated in response to injury only in fetal sheep postinjury. Our results demonstrate the power and relevance of the ovine fetal cartilage regeneration model presented here for the first time. The identification of previously unrecognized modulatory proteins that plausibly affect the healing process holds great promise for potential therapeutic interventions.

Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Degeneration via Estrogen Receptor Alpha in Female Mice.

Temporomandibular joint degenerative disease (TMJ-DD) is a chronic form of TMJ disorder that specifically afflicts people over the age of 40 and targets women at a higher rate than men. Prevalence of TMJ-DD in this population suggests that estrogen loss plays a role in the disease pathogenesis. Thus, the goal of the present study was to determine the role of estrogen on chondrogenesis and homeostasis via estrogen receptor alpha (ERα) during growth and maturity of the joint. Young and mature WT and ERαKO female mice were subjected to ovariectomy procedures and then given placebo or estradiol treatment. The effect of estrogen via ERα on fibrocartilage morphology, matrix production, and protease activity was assessed. In the young mice, estrogen via ERα promoted mandibular condylar fibrocartilage chondrogenesis partly by inhibiting the canonical Wnt signaling pathway through upregulation of sclerostin (Sost). In the mature mice, protease activity was partly inhibited with estrogen treatment via the upregulation and activity of protease inhibitor 15 (Pi15) and alpha-2-macroglobulin (A2m). The results from this work provide a mechanistic understanding of estradiol on TMJ growth and homeostasis and can be utilized for development of therapeutic targets to promote regeneration and inhibit degeneration of the mandibular condylar fibrocartilage.

Part II: Temporomandibular Joint (TMJ)-Regeneration, Degeneration, and Adaptation.

PURPOSE OF REVIEW: Elucidate temporomandibular joint (TMJ) development and pathophysiology relative to regeneration, degeneration, and adaption. RECENT FINDINGS: The pharyngeal arch produces a highly conserved stomatognathic system that supports airway and masticatory function. An induced subperiosteal layer of fibrocartilage cushions TMJ functional and parafunctional loads. If the fibrocartilage disc is present, a fractured mandibular condyle (MC) regenerates near the eminence of the fossa via a blastema emanating from the medial periosteal surface of the ramus. TMJ degenerative joint disease (DJD) is a relatively painless osteoarthrosis, resulting in extensive sclerosis, disc destruction, and lytic lesions. Facial form and symmetry may be affected, but the residual bone is vital because distraction continues to lengthen the MC with anabolic bone modeling. Extensive TMJ adaptive, healing, and regenerative potential maintains optimal, life support functions over a lifetime. Unique aspects of TMJ development, function, and pathophysiology may be useful for innovative management of other joints.

Novel engineered tendon-fibrocartilage-bone composite with cyclic tension for rotator cuff repair.

Surgical repair of rotator cuff tears presents a significant clinical challenge with high failure rates and inferior functional outcomes. Graft augmentation improves repair outcomes; however, currently available grafting materials have limitations. Although cell-seeded decellularized tendon slices may facilitate cell infiltration, promote tendon incorporation, and preserve original mechanical strength, the unique fibrocartilage zone is yet to be successfully reestablished. In this study, we investigated the biological and mechanical properties of an engineered tendon-fibrocartilage-bone composite (TFBC) with cyclic tension (3% strain; 0.2 Hz). Decellularized TFBCs seeded with bone marrow-derived mesenchymal stem cell (BMSCs) sheets and subjected to mechanical stimulation for up to 7 days were characterised by histology, immunohistochemistry, scanning electron microscopy, mechanical testing, and transcriptional regulation. The decellularized TFBC maintained native enthesis structure and properties. Mechanically stimulated TFBC-BMSC constructs displayed increased cell migration after 7 days of culture compared with static groups. The seeded cell sheet not only integrated well with tendon scaffold but also distributed homogeneously and aligned to the direction of stretch under dynamic culture. Developmental genes were regulated including scleraxis, which was significantly upregulated with mechanical stimulation. The Young's modulus of the cell-seeded constructs was significantly higher compared with the noncell-seeded controls. In conclusion, the results of this study reveal that the TFBC-BMSC composite provides an ideal multilayer construct for cell seeding and growth, with mechanical preconditioning further enhances cell penetration and differentiation. The BMSC cell sheet revitalised TFBC in conjunction with mechanical stimulation could serve as a novel and primed biological patch to improve rotator cuff repair.

Fibrocartilaginous metaplasia identified in the long head of the biceps brachii.

BACKGROUND: In the glenohumeral joint, the long head of biceps brachii (LHBB) is exposed to tension and compression loading. The short head of biceps brachii (SHBB) works only in tension. It is known that tendon under compression might develop fibrocartilaginous metaplasia that improves the resistance to compression but reduces the resistance to tension. This study evaluated the presence of cartilage in LHBB and SHBB samples, supporting its possible role in tendon tear. METHODS: Between 2014 and 2016, 13 samples of LHBB and SHBB were collected during surgery for shoulder instability, glenohumeral arthritis, and massive rotator cuff tears. The samples were stained with hematoxylin and eosin, safranin-O, and Alcian blue (pH 1.0) for light microscopy. Immunohistochemistry was performed using anti-S100, anti-collagen I and II, and anti-tenascin-C antibodies. RESULTS: Histochemistry: LHBB samples showed matrix disorganization, with clusters of chondrocyte surrounded by collagen fibers and glycosaminoglycans. Safranin-O showed evident metachromasia. SHBB samples did not show any matrix disorganization or cartilaginous metaplasia. Immunohistochemistry: In all LHBB samples, anti-S100 and anti-collagen II showed cartilage in proximity of the tendon tear. Tenascin C immunostained closely to the disorganized matrix areas. SHBB, however, showed no positive areas for S-100, anti-collagen II, or tenascin C. CONCLUSIONS: According to our results, we hypothesize that the repeated stimulation in compression may induce the formation of fibrous cartilage. However, to date its role in tendon pathology remains to be clearly defined.

Excision of Labral Amorphous Calcification as a Part of Hip Arthroscopy-Clinical Outcomes in a Matched-Controlled Study.

PURPOSE: To evaluate clinical outcomes, demographics, and radiographic findings for patients whose hip arthroscopies involved amorphous calcification (AC) excision and to compare them with a control group with no AC and with the general population regarding diabetes mellitus and hypothyroidism. METHODS: Patients who underwent primary hip arthroscopy involving surgical excision of AC deposit in the anterosuperior labralcapsular recess between October 2008 and July 2014 were reviewed. Demographics, radiographic findings, intraoperative findings, and procedures were reviewed. Minimum follow-up was 2 years and included visual analog scale for pain, patient satisfaction, and the following patient-reported outcome scores: modified Harris hip score, hip outcomes score sport-specific subscale, and nonarthritic hip score. These patients were matched (1:2 ratio) to patients who underwent hip arthroscopy with no AC using the following matching criteria: age at surgery ± 5 years, body mass index ± 5, gender, type of labral treatment, and type of capsular treatment. RESULTS: We reviewed 12 cases in 11 female patients. Mean latest follow-up scores improved from 64.0 to 83.4 (P = .003) for modified Harris hip score, from 57.6 to 80.6 (P < .001) for nonarthritic hip score, from 35.4 to 62.7 (P = .021) for hip outcomes score sport-specific subscale, and from 6.4 to 2.8 (P = .016) for visual analog scale. The survivorship rate was 91.7%, with one hip converting to total hip arthroplasty. Mean patient satisfaction was 8.4 ± 2.3. Six hips of the 12 (50%) had clock face localization of the AC. They were all between 11 and 12 with a mean of 12:30. Postoperative radiographic findings showed no subsequent AC in all 12 hips. No complications or revisions were reported. There were no significant differences between the AC group and the control group. CONCLUSIONS: The treatment of AC as part of hip arthroscopy for labral tear and femoro-acetabular impingement is safe and has favorable and similar outcomes compared with a control group at minimum 2-year follow-up. Female gender may be a risk factor for the development of AC. There is no strong evidence that AC should be debrided. LEVEL OF EVIDENCE: Level III, case control study.