Human Cartilage-Derived Progenitors Resist Terminal Differentiation and Require CXCR4 Activation to Successfully Bridge Meniscus Tissue Tears.

Meniscus injuries are among the most common orthopedic injuries. Tears in the inner one-third of the meniscus heal poorly and present a significant clinical challenge. In this study, we hypothesized that progenitor cells from healthy human articular cartilage (chondroprogenitor cells [C-PCs]) may be more suitable than bone-marrow mesenchymal stem cells (BM-MSCs) to mediate bridging and reintegration of fibrocartilage tissue tears in meniscus. C-PCs were isolated from healthy human articular cartilage based on their expression of mesenchymal stem/progenitor marker activated leukocyte cell adhesion molecule (ALCAM) (CD166). Our findings revealed that healthy human C-PCs are CD166+, CD90+, CD54+, CD106- cells with multilineage differentiation potential, and elevated basal expression of chondrogenesis marker SOX-9. We show that, similar to BM-MSCs, C-PCs are responsive to the chemokine stromal cell-derived factor-1 (SDF-1) and they can successfully migrate to the area of meniscal tissue damage promoting collagen bridging across inner meniscal tears. In contrast to BM-MSCs, C-PCs maintained reduced expression of cellular hypertrophy marker collagen X in monolayer culture and in an explant organ culture model of meniscus repair. Treatment of C-PCs with SDF-1/CXCR4 pathway inhibitor AMD3100 disrupted cell localization to area of injury and prevented meniscus tissue bridging thereby indicating that the SDF-1/CXCR4 axis is an important mediator of this repair process. This study suggests that C-PCs from healthy human cartilage may potentially be a useful tool for fibrocartilage tissue repair/regeneration because they resist cellular hypertrophy and mobilize in response to chemokine signaling. Stem Cells 2019;37:102-114.

Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells.

Chondrocyte hypertrophy is a hallmark of osteoarthritis (OA) pathology. In the present study, we elucidated the mechanism underlying the relationship between the hypertrophy/apoptotic phenotype and OA pathogenesis in bone marrow-derived mesenchymal stem cells (BM-MSCs) via gene targeting of distal-less homeobox 5 (DLX5). Our primary objectives were (1) to determine whether DLX5 is a predictive biomarker of cellular hypertrophy in human osteoarthritic tissues; (2) To determine whether modulating DLX5 activity can regulate cell hypertrophy in mesenchymal stem/progenitor cells from marrow and cartilage. Whole transcriptome sequencing was performed to identify differences in the RNA expression profile between human-cartilage-derived mesenchymal progenitors (C-PCs) and bone-marrow-derived mesenchymal progenitors (BM-MSCs). Ingenuity Pathway Analysis (IPA) software was used to compare molecular pathways known to regulate hypertrophic terminal cell differentiation. RT-qPCR was used to measure DLX5 and hypertrophy marker COL10 in healthy human chondrocytes and OA chondrocytes. DLX5 was knocked down or overexpressed in BM-MSCs and C-PCs and RT-qPCR were used to measure the expression of hypertrophy/terminal differentiation markers following DLX5 modulation. Apoptotic cell activity was characterized by immunostaining for cleaved caspase 3/7. We demonstrate that DLX5 and downstream hypertrophy markers were significantly upregulated in BM-MSCs, relative to C-PCs. DLX5 and COL10 were also significantly upregulated in cells from OA knee joint tissues, relative to normal non-arthritic joint tissues. Knocking down DLX5 in BM-MSCs inhibited cell hypertrophy and apoptotic activity without attenuating their chondrogenic potential. Overexpression of DLX5 in C-PCs stimulated hypertrophy markers and increased apoptotic cell activity. Modulating DLX5 activity regulates cell hypertrophy and apoptosis in BM-MSCs and C-PCs. These findings suggest that DLX5 is a biomarker of OA changes in human knee joint tissues and confirms the DLX5 mechanism contributes to hypertrophy and apoptosis in BM-MSCs.

Estimates of Golf-Related Upper Extremity Injuries in the United States: A 10-Year Epidemiology Study (2011-2020).

BACKGROUND: Golf is one of the most popular sports in the United States (US) and is played by participants of all ages and skill level. Given the popularity and sport-specific demands on the upper torso, golf poses a considerable risk for upper extremity (UE) injuries. Therefore, the aim of the current study was to (1) determine the incidence rate of UE golf injuries presenting to emergency departments (EDs) in the US, (2) determine the most commonly injured body parts and mechanisms of injury, and (3) compare current injury epidemiology with previous trends in the literature. HYPOTHESIS: Male sex, bimodal age extremes (young and elderly), and utilization of golf carts (vs walking) are associated with a higher incidence of golf-related UE injuries. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 3. METHODS: The National Electronic Injury Surveillance System (NEISS) is a statistically validated injury surveillance system that collects data from ED visits as a representative probability sample of hospitals in the US. We queried the NEISS for the years 2011 to 2020 to examine the following variables for golf-related UE injuries: sociodemographic, diagnosis, body part, and mechanism of injury. RESULTS: From 2011 to 2020, there were a total of 1862 golf-related UE injuries presenting to participating EDs, which correlates to an estimated 70,868 total injuries. Overall, male golf players were disproportionately affected (69.2%) versus female golf players (30.8%) and the most commonly injured age groups were those aged >60 and 10 to 19 years. The most common injuries included fractures (26.8%), strains/sprains (23.4%), and soft tissue injuries (15.9%). The joints injured most frequently were the shoulder (24.8%), wrist (15.6%), and joints in the hand (12.0%). The most common mechanisms of injury were cart accidents (44.63%), falling/tripping (29.22%), and golf club swinging/mechanics (10.37%). CONCLUSION: Golf-related UE injuries can be acute or due to chronic overuse. Male athletes >60 years of age were the population most commonly presenting to the ED with a golf-related injury. Further, the shoulder, forearm, and wrist were most commonly injured. These findings are consistent with previous epidemiological trends in the literature. Interventions to reduce the incidence of injury should be sport-specific and focus primarily on equipment and golf cart safety and swing modification to optimize the biomechanical function of the UEs. CLINICAL RELEVANCE: Our findings indicate that golf-related injury prevention programs should target UE injuries, particularly among young (<19) and older (>60 years) golfers with poor swing mechanics.

Stable human cartilage progenitor cell line stimulates healing of meniscal tears and attenuates post-traumatic osteoarthritis.

Meniscal tearing in the knee increases the risk of post-traumatic osteoarthritis (OA) in patients. The therapeutic application of tissue-specific mesenchymal progenitor cells is currently being investigated as an emerging biologic strategy to help improve healing of musculoskeletal tissues like meniscal fibrocartilage and articular hyaline cartilage. However, many of these approaches involve isolating cells from healthy tissues, and the low yield of rare progenitor populations (< 1% of total cells residing in tissues) can make finding a readily available cell source for therapeutic use a significant logistical challenge. In the present study, we investigated the therapeutic efficacy of using expanded cartilage-derived and bone marrow-derived progenitor cell lines, which were stabilized using retroviral SV40, for repair of meniscus injury in a rodent model. Our findings indicate that these cell lines express the same cell surface marker phenotype of primary cells (CD54+, CD90+, CD105+, CD166+), and that they exhibit improved proliferative capacity that is suitable for extensive expansion. Skeletally mature male athymic rats treated with 3.2 million cartilage-derived progenitor cell line exhibited approximately 79% greater meniscal tear reintegration/healing, compared to injured animals that left untreated, and 76% greater compared to animals treated with the same number of marrow-derived stromal cells. Histological analysis of articular surfaces also showed that cartilage-derived progenitor cell line treated animals exhibited reduced post-traumatic OA associated articular cartilage degeneration. Stable cell line treatment did not cause tumor formation or off-target engraftment in animals. Taken together, we present a proof-of-concept study demonstrating, for the first time, that intra-articular injection of a stable human cartilage-derived progenitor cell line stimulates meniscus tear healing and provide chondroprotection in an animal model. These outcomes suggest that the use of stable cell lines may help overcome cell source limitations for cell-based medicine.

Shoulder dislocations among high school-aged and college-aged athletes in the United States: an epidemiologic analysis.

HYPOTHESIS/BACKGROUND: Shoulder dislocations are common orthopedic injuries due to the mobile nature of the glenohumeral joint. High school and collegiate athletes are at particularly high risk for sustaining a dislocation event. Despite the prevalence of these injuries, there is a paucity in the literature regarding incidence of sports-related shoulder dislocations and mechanism of injury within these populations. Therefore, the aim of the present study was to (1) determine the incidence rate of shoulder dislocations in high school-aged and collegiate-aged athletes presenting to emergency departments (EDs) in the United States; (2) to determine the most common sports associated with shoulder dislocations; and (3) to compare the current rates and risk factors for shoulder dislocation with previous trends. METHODS: The National Electronic Injury Surveillance System is a statistically validated injury surveillance system that collects data from ED visits as a representative probability sample of hospitals in the United States. We queried the National Electronic Injury Surveillance System for the years 2015-2019 to examine the following variables for sports-related shoulder dislocations: patient age (high school = 13-17 years of age; collegiate = 18-23 years of age), sex, year of admission, and sport type. Using a weighted multiplier, annual incidence rates were estimated based on the US Census estimates and injury rates were compared by sex and age group across the study period. RESULTS: From 2015 to 2019, there were a total of 1329 athletic-related shoulder dislocations that presented to participating EDs. Of these, 698 (52.5%) shoulder dislocations occurred in collegiate athletes, while 631 (47.5%) occurred in high school athletes. Using weighted and adjusted estimates automatically generated by the National Electronic Injury Surveillance System database, this translates to 89,511 total athletic-related shoulder dislocations across the United States (95% confidence interval lower bound 68,224; 95% confidence interval upper bound 110,798). Male athletes demonstrated a higher proportion of shoulder dislocations (87%) than female athletes (13%). The most common sport-specific mechanisms of traumatic shoulder dislocation were basketball (24.1%), football (21%), soccer (7.1%), baseball (7.1%), and weightlifting (3.3%). CONCLUSION: Sports-related shoulder dislocations are frequent in high school-aged and college-aged athletes presenting to the ED. Interventions to reduce incidence of injury should be sport-specific and focus on those participating in contact and noncontact sports. Male athletes have disproportionately higher rates of dislocation. These findings are consistent with the previous epidemiologic trends in the literature that have examined the incidence of shoulder dislocations in this population.

Obesity alters the collagen organization and mechanical properties of murine cartilage.

Osteoarthritis is a debilitating disease characterized by cartilage degradation and altered cartilage mechanical properties. Furthermore, it is well established that obesity is a primary risk factor for osteoarthritis. The purpose of this study was to investigate the influence of obesity on the mechanical properties of murine knee cartilage. Two-month old wild type mice were fed either a normal diet or a high fat diet for 16 weeks. Atomic force microscopy-based nanoindentation was used to quantify the effective indentation modulus of medial femoral condyle cartilage. Osteoarthritis progression was graded using the OARSI system. Additionally, collagen organization was evaluated with picrosirius red staining imaged using polarized light microscopy. Significant differences between diet groups were assessed using t tests with p < 0.05. Following 16 weeks of a high fat diet, no significant differences in OARSI scoring were detected. However, we detected a significant difference in the effective indentation modulus between diet groups. The reduction in cartilage stiffness is likely the result of disrupted collagen organization in the superficial zone, as indicated by altered birefringence on polarized light microscopy. Collectively, these results suggest obesity is associated with changes in knee cartilage mechanical properties, which may be an early indicator of disease progression.

Meniscus Repair and Regeneration: A Systematic Review from a Basic and Translational Science Perspective.

Meniscus injuries are among the most common athletic injuries and result in functional impairment in the knee. Repair is crucial for pain relief and prevention of degenerative joint diseases like osteoarthritis. Current treatments, however, do not produce long-term improvements. Thus, recent research has been investigating new therapeutic options for regenerating injured meniscal tissue. This review comprehensively details the current methodologies being explored in the basic sciences to stimulate better meniscus injury repair. Furthermore, it describes how these preclinical strategies may improve current paradigms of how meniscal injuries are clinically treated through a unique and alternative perspective to traditional clinical methodology.

Characterization and Fate of Unpublished Research Articles Reported by Orthopedic Surgery Residency Applicants.

OBJECTIVE: As the competitiveness of matching to an orthopedic residency continues to increase, applicants attempt to bolster their application by participating in research activities. However, due to the brief duration of medical school, applicants' articles may not be published at the time of applying. The purpose of this study was to identify projects that were listed under "publications-other than published" within Electronic Residency Application System (ERAS) applications of prospective orthopedic surgery residents to determine the rate and time of these projects to future publication in a peer-reviewed journal. Program directors can use this information to help interpret the importance of such articles on the applications of future residency candidates. DESIGN: Retrospective study of prospective residents' applications to a single orthopedic residency program during the 2014 to 2015 application cycle were reviewed to identify articles designated as "other than published." Articles which advanced to official publication were confirmed using the Embase, PubMed, and Google Scholar databases. Applicant and article characteristics were recorded to identify variables associated with an increased proportion of articles that were able to be confirmed. PARTICIPANTS: Prospective residents to a single orthopedic residency program during the 2014 to 2015 application cycle. RESULTS: A total of 1957 article titles were listed amongst 563 applicants, with 48% of applicants (n = 271) having at least one peer-reviewed article listed as "other than published." Overall, 34.2% (709) of the articles were designated as being unpublished including 208 listed as accepted/in-press and 501 listed as submitted/under review. Of the accepted/in-press articles, 90.7% (n = 189) were able to be confirmed as successfully published papers, compared to 63.4% (n = 318) of articles designated as submitted/under review (p < 0.001). Factors predictive of articles which advanced to official publication were being accepted/in-press at the time of applying, a lower United States Medical Licensing Exam (USMLE) Step 1 score, and articles on orthopedic topics. CONCLUSIONS: Nearly one-half of orthopedic residency applicants report unpublished research articles on their ERAS application. While 90.7% of the articles listed as being accepted/ in press were eventually published, less than two-thirds of the articles designated as being in submission/under-review progressed to official publication.

Epidemiology of shoulder and elbow injuries in National Collegiate Athletic Association wrestlers, 2009-2010 through 2013-2014.

OBJECTIVES: Examination of the incidence of shoulder and elbow injuries in the collegiate wrestling population is limited. Therefore, we sought to determine the incidence of shoulder and elbow injuries in wrestlers competing in the National Collegiate Athletic Association (NCAA), and investigate the risk factors involved. METHODS: All shoulder and elbow injuries in wrestlers from the 2009-2010 through 2013-2014 academic years in the NCAA Injury Surveillance Program database were extracted. The incidence of different injuries, sports, activity, time-in-game, competition status, and injury characteristics was recorded. Risk-ratios were calculated to determine risk factors for injury. RESULTS: Collegiate wrestlers had an incidence of 21.59 shoulder and elbow injuries per 10,000 athletic exposures (AEs). The most frequent injury types included elbow ulnar collateral ligament tears, shoulder impingement, and acromioclavicular joint sprains, although there was significant variability. Freshman collegiate wrestlers suffered a significantly higher percentage of shoulder and elbow injuries than more senior athletes, signifying an association between experience and injury risk. There was a 4-fold higher incidence of injury during competition. Injuries were significantly more likely to occur later in the match, with a 2.5-fold increased risk compared with early. While 26.8% of wrestlers were out of play for at least 14 days, only 5.9% of all injuries required surgery. Lastly, Division I collegiate wrestlers had the highest overall injury rate. CONCLUSIONS: Collegiate wrestlers have a high incidence of shoulder and elbow injury, with specific risk factors identified here. This at-risk patient population should be monitored closely for signs of fatigue, which may leave them susceptible to injury. Further prospective investigation of wrestling injuries with a special attention to injury prevention in higher risk athletes are needed to further validate these findings.