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  • 1
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 82, No. 2 ( 2023-02), p. 272-282
    Abstract: Synovium is acutely affected following joint trauma and contributes to post-traumatic osteoarthritis (PTOA) progression. Little is known about discrete cell types and molecular mechanisms in PTOA synovium. We aimed to describe synovial cell populations and their dynamics in PTOA, with a focus on fibroblasts. We also sought to define mechanisms of synovial Wnt/β-catenin signalling, given its emerging importance in arthritis. Methods We subjected mice to non-invasive anterior cruciate ligament rupture as a model of human joint injury. We performed single-cell RNA-sequencing to assess synovial cell populations, subjected Wnt-GFP reporter mice to joint injury to study Wnt-active cells, and performed intra-articular injections of the Wnt agonist R-spondin 2 (Rspo2) to assess whether gain of function induced pathologies characteristic of PTOA. Lastly, we used cultured fibroblasts, macrophages and chondrocytes to study how Rspo2 orchestrates crosstalk between joint cell types. Results We uncovered seven distinct functional subsets of synovial fibroblasts in healthy and injured synovium, and defined their temporal dynamics in early and established PTOA. Wnt/β-catenin signalling was overactive in PTOA synovium, and Rspo2 was strongly induced after injury and secreted exclusively by Prg4 hi lining fibroblasts. Trajectory analyses predicted that Prg4 hi lining fibroblasts arise from a pool of Dpp4+ mesenchymal progenitors in synovium, with SOX5 identified as a potential regulator of this emergence. We also showed that Rspo2 orchestrated pathological crosstalk between synovial fibroblasts, macrophages and chondrocytes. Conclusions Synovial fibroblasts assume distinct functional identities during PTOA in mice, and Prg4 hi lining fibroblasts secrete Rspo2 that may drive pathological joint crosstalk after injury.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    RVK:
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1481557-6
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  • 2
    Online Resource
    Online Resource
    SAGE Publications ; 2020
    In:  The American Journal of Sports Medicine Vol. 48, No. 13 ( 2020-11), p. 3245-3254
    In: The American Journal of Sports Medicine, SAGE Publications, Vol. 48, No. 13 ( 2020-11), p. 3245-3254
    Abstract: Blood flow restriction therapy (BFRT) has been increasingly applied to improve athletic performance and injury recovery. Validation of BFRT has lagged behind commercialization, and currently the mechanism by which this therapy acts is unknown. BFRT is one type of ischemic therapy, which involves exercising with blood flow restriction. Repetitive restriction of muscle blood flow (RRMBF) is another ischemic therapy type, which does not include exercise. Hypothesis/Purpose: The purpose was to develop a rat model of ischemic therapy, characterize changes to muscle contractility, and evaluate local and systemic biochemical and histologic responses of 2 ischemic therapy types. We hypothesized that ischemic therapy would improve muscle mass and strength as compared with the control group. Study Design: Controlled laboratory study. Methods: Four groups of 10 Sprague-Dawley rats were established: control, stimulation, RRMBF, and BFRT. One hindlimb of each subject underwent 8 treatment sessions over 4 weeks. To simulate exercise, the stimulation group underwent peroneal nerve stimulation for 2 minutes. The RRMBF group used a pneumatic cuff inflated to 100 mm Hg with a 48-minute protocol. The BFRT group involved 100–mm Hg pneumatic cuff inflation and peroneal nerve stimulation for a 5-minute protocol. Four methods of evaluation were performed: in vivo contractility testing, histology, immunohistochemistry, and ELISA. Analysis of variance with post hoc Tukey test and linear mixed effects modeling were used to compare the treatment groups. Results: There was no difference in muscle mass among groups ( P = .40) or between hindlimbs ( P = .73). In vivo contractility testing showed no difference in maximum contractile force among groups ( P = .64) or between hindlimbs ( P = .30). On histology, myocyte cross-sectional area was not different among groups ( P = .55) or between hindlimbs ( P = .44). Pax7 immunohistochemistry demonstrated no difference in muscle satellite cell density among groups ( P = .06) or between hindlimbs ( P = .046). ELISA demonstrated the RRMBF group as eliciting elevated GH levels as compared with the other groups ( P 〈 .001). Conclusion: Ischemic therapy did not induce gains in muscle mass, contractility strength, fiber cross-sectional area, or satellite cell density locally or systemically in this model, although the RRMBF group did have elevated GH levels on ELISA. Clinical Relevance: This animal model does not support ischemic therapy as a method to improve muscle mass, function, or satellite cell density.
    Type of Medium: Online Resource
    ISSN: 0363-5465 , 1552-3365
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2020
    detail.hit.zdb_id: 2063945-4
    SSG: 31
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  • 3
    In: Osteoarthritis and Cartilage, Elsevier BV, ( 2023-9)
    Type of Medium: Online Resource
    ISSN: 1063-4584
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2002544-0
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  • 4
    Online Resource
    Online Resource
    Frontiers Media SA ; 2024
    In:  Frontiers in Neuroanatomy Vol. 18 ( 2024-7-15)
    In: Frontiers in Neuroanatomy, Frontiers Media SA, Vol. 18 ( 2024-7-15)
    Abstract: Knee joints are densely innervated by nociceptors. In human knees and rodent models, sprouting of nociceptors has been reported in late-stage osteoarthritis (OA). Here, we sought to describe progressive nociceptor remodeling in early and late-stage OA, using four distinct experimental mouse models. Methods Sham surgery, destabilization of the medial meniscus (DMM), partial meniscectomy (PMX), or non-invasive anterior cruciate ligament rupture (ACLR) was performed in the right knee of 10-12-week old male C57BL/6 Na V 1.8-tdTomato mice. Mice were euthanized (1) 4, 8 or 16 weeks after DMM or sham surgery; (2) 4 or 12 weeks after PMX or sham; (3) 1 or 4 weeks after ACLR injury or sham. Additionally, a cohort of naïve male wildtype mice was evaluated at age 6 and 24 months. Mid-joint cryosections were assessed qualitatively and quantitatively for Na V 1.8+ or PGP9.5+ innervation. Cartilage damage, synovitis, and osteophytes were assessed. Results Progressive OA developed in the medial compartment after DMM, PMX, and ACLR. Synovitis and associated neo-innervation of the synovium by nociceptors peaked in early-stage OA. In the subchondral bone, channels containing sprouting nociceptors appeared early, and progressed with worsening joint damage. Two-year old mice developed primary OA in the medial and the lateral compartment, accompanied by nociceptor sprouting in the synovium and the subchondral bone. All four models showed increased nerve signal in osteophytes. Conclusion These findings suggest that anatomical neuroplasticity of nociceptors is intrinsic to OA pathology. The detailed description of innervation of the OA joint and its relationship to joint damage might help in understanding OA pain.
    Type of Medium: Online Resource
    ISSN: 1662-5129
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2024
    detail.hit.zdb_id: 2452969-2
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  • 5
    In: Journal of Orthopaedic Research, Wiley, Vol. 39, No. 9 ( 2021-09), p. 1965-1976
    Abstract: Assess acute alterations in bone turnover, microstructure, and histomorphometry following noninvasive anterior cruciate ligament rupture (ACLR). Twelve female Lewis rats were randomized to receive noninvasive ACLR or Sham loading ( n  = 6/group). In vivo μCT was performed at 3, 7, 10, and 14 days postinjury to quantify compartment‐dependent subchondral (SCB) and epiphyseal trabecular bone remodeling. Near‐infrared (NIR) molecular imaging was used to measure in vivo bone anabolism (800 CW BoneTag) and catabolism (Cat K 680 FAST). Metaphyseal bone remodeling and articular cartilage morphology was quantified using ex vivo μCT and contrast‐enhanced µCT, respectively. Calcein‐based dynamic histomorphometry was used to quantify bone formation. OARSI scoring was used to assess joint degeneration, and osteoclast number was quantified on TRAP stained‐sections. ACLR induced acute catabolic bone remodeling in subchondral, epiphyseal, and metaphyseal compartments. Thinning of medial femoral condyle (MFC) SCB was observed as early as 7 days postinjury, while lateral femoral condyles (LFCs) exhibited SCB gains. Trabecular thinning was observed in MFC epiphyseal bone, with minimal changes to LFC. NIR imaging demonstrated immediate and sustained reduction of bone anabolism (~15%–20%), and a ~32% increase in bone catabolism at 14 days, compared to contralateral limbs. These findings were corroborated by reduced bone formation rate and increased osteoclast numbers, observed histologically. ACLR‐injured femora had significantly elevated OARSI score, cartilage thickness, and cartilage surface deviation. ACL rupture induces immediate and sustained reduction of bone anabolism and overactivation of bone catabolism, with mild‐to‐moderate articular cartilage damage at 14 days postinjury.
    Type of Medium: Online Resource
    ISSN: 0736-0266 , 1554-527X
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2050452-4
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  • 6
    In: Bone, Elsevier BV, Vol. 137 ( 2020-08), p. 115417-
    Type of Medium: Online Resource
    ISSN: 8756-3282
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1496324-3
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  • 7
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 132, No. 11 ( 2022-6-1)
    Type of Medium: Online Resource
    ISSN: 1558-8238
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2022
    detail.hit.zdb_id: 2018375-6
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  • 8
    Online Resource
    Online Resource
    SAGE Publications ; 2023
    In:  HSS Journal®: The Musculoskeletal Journal of Hospital for Special Surgery Vol. 19, No. 1 ( 2023-02), p. 97-106
    In: HSS Journal®: The Musculoskeletal Journal of Hospital for Special Surgery, SAGE Publications, Vol. 19, No. 1 ( 2023-02), p. 97-106
    Abstract: Background: Patients with symptomatic femoroacetabular impingement (FAI) have hip strength deficits, instability, and increased risk for concomitant injury. While surgical intervention is an effective method of treatment for FAI, more information is needed about the recovery process. Purposes: We sought to understand how patients with FAI recover from surgical correction in the short term. Do patients’ perceptions of improvement correspond with measured improvements in hip strength? Methods: We conducted a prospective cohort study of 17 patients (11 male, age range: 16–38 years) who were diagnosed with symptomatic FAI at a single surgeon’s practice. Hip strength (flexion, extension, and abduction) was measured preoperatively and at 14, 26, and 52 weeks postoperatively. Patient-reported outcomes using the modified Harris Hip Score (mHHS) and Hip Outcome Osteoarthritis Score (HOOS) subscales were measured at the same time points and at 2 weeks postoperatively. Results: Compared with preoperative values, there was a significant increase in postoperative values at 26 and 52 weeks in normalized isokinetic hip extension (29% and 38%, respectively) and normalized hip abduction (48% and 55%, respectively). No differences in strength were observed at 14 weeks. Modified Harris Hip Score and all HOOS subscales were decreased by 2 weeks postoperatively, and by 14 weeks mHHS improved by 21%, and HOOS subscales improved as well (activities of daily living by 18%, pain by 34%, quality of life by 69%, sport and recreation by 36%, and symptoms by 28%). Conclusion: We observed that patient-reported outcomes including symptoms, function, and satisfaction improved at 14 weeks, while objective measures of hip strength improved at 26 weeks following surgical correction of FAI. More rigorous study is indicated.
    Type of Medium: Online Resource
    ISSN: 1556-3316 , 1556-3324
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2023
    detail.hit.zdb_id: 2210985-7
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  • 9
    In: Orthopaedic Journal of Sports Medicine, SAGE Publications, Vol. 8, No. 7_suppl6 ( 2020-07-01), p. 2325967120S0043-
    Abstract: Patients with Femoroacetabular impingement (FAI) have been shown to have elevated circulating biomarkers of inflammation and cartilage catabolism, but little is known about whether corrective surgical intervention improves objective measures of hip strength and inflammation. This study measured several variables including pain, function, quality of life, symptoms, hip strength, and inflammatory and cartilage biomarkers in a cohort of subjects undergoing FAI surgery and postoperative (postop) rehabilitation. We hypothesized that surgical FAI repair and completion of a postop rehabilitation program will significantly improve patient reported outcomes (PROs), increase hip flexion and abduction strength measures, and decrease biomarkers of inflammation and cartilage degradation. Methods: This study was approved by the University of Michigan Medical School IRB (HUM00055335). Male and female patients aged 16-40 years of age, with symptomatic FAI diagnosed by concordant history, physical examination, and imaging findings were eligible for inclusion. Subjects who have undergone previous hip surgery, have a global overcoverage deformity, dysplasia, or degenerative chondral changes greater than Tonnis grade I were excluded. A single, fellowship trained, sports medicine orthopaedic surgeon performed all surgical procedures, and patients underwent a standardized postop rehabilitation program. HOOS questionnaires were assessed at each subject’s preoperative visit (preop), and at 2, 14, 26, and 52 weeks postop. Hip flexion, abduction, and extension were measured at each time point using a BioDex isokinetic dynamometer. High sensitivity C-reactive protein (HS-CRP) and cartilage oligomeric matrix protein (COMP) were measured in plasma using ELISAs. Differences between preop and postop time points were assessed using a mixed-effects model, and data are reported as mean±95% CI. Results: A total of 11 males and 6 females completed the study. Mean age of subjects was 25.2±3.8 years (range 16.0-38.0 years) and BMI of 24.2±2.0 kg/m2 (range 18.1-33.6 kg/m2). For most HOOS subscales, there was a decrease in score at 2 weeks postop, and by 14 weeks activities of daily living (ADL) improved by 18%, pain by 34%, quality of life by 69%, sport and recreation by 36%, and symptoms by 28% compared to preop values (Figure 1A-E). These improvements in HOOS subscales persisted for the duration of the study period (Figure 1A-E). No differences in hip flexion strength were observed, while extension was 20% and 31% significantly higher than preop values at 26 and 52 weeks, and for abduction patients were 34% stronger than preop values at 52 weeks. No differences in HS-CRP or COMP were observed (Figure 1F-J). Conclusion: In support of our hypothesis, we observed significant improvements in PROs of hip function, although changes in PROs preceded improvements in objective measures of hip extension and abduction strength. Despite improvements in other planes, no changes in hip flexion were observed. Plasma biomarkers of hip inflammation and cartilage turnover were not reduced by surgical intervention and rehabilitation. FAI surgery and postop rehabilitation is effective at treating pain, and improving patient reported quality of life and symptoms, with modest improvements in hip strength. However, the surgical correction of pathological hip anatomy and improvements in hip strength did not lead to significant differences in markers of inflammation or cartilage turnover.
    Type of Medium: Online Resource
    ISSN: 2325-9671 , 2325-9671
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2020
    detail.hit.zdb_id: 2706251-X
    SSG: 31
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  • 10
    In: BMC Pregnancy and Childbirth, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2020-12)
    Abstract: Pelvic floor muscles (PFM) and rectus abdominis muscles (RAM) of pregnant diabetic rats exhibit atrophy, co-localization of fast and slow fibers and an increased collagen type I/III ratio. However, the role of similar PFM or RAM hyperglycemic-related myopathy in women with gestational diabetes mellitus (GDM) remains poorly investigated. This study aims to assess the frequency of pelvic floor muscle disorders and pregnancy-specific urinary incontinence (PS-UI) 12 months after the Cesarean (C) section in women with GDM. Specifically, differences in PFM/RAM hyperglycemic myopathy will be evaluated. Methods The Diamater is an ongoing cohort study of four groups of 59 pregnant women each from the Perinatal Diabetes Research Centre (PDRC), Botucatu Medical School (FMB)-UNESP (São Paulo State University), Brazil. Diagnosis of GDM and PS-UI will be made at 24–26 weeks, with a follow-up at 34–38 weeks of gestation. Inclusion in the study will occur at the time of C-section, and patients will be followed at 24–48 h, 6 weeks and 6 and 12 months postpartum. Study groups will be classified as (1) GDM plus PS-UI; (2) GDM without PS-UI; (3) Non-GDM plus PS-UI; and (4) Non-GDM without PS-UI. We will analyze relationships between GDM, PS-UI and hyperglycemic myopathy at 12 months after C-section. The mediator variables to be evaluated include digital palpation, vaginal squeeze pressure, 3D pelvic floor ultrasound, and 3D RAM ultrasound. RAM samples obtained during C-section will be analyzed for ex-vivo contractility, morphological, molecular and OMICS profiles to further characterize the hyperglycemic myopathy. Additional variables to be evaluated include maternal age, socioeconomic status, educational level, ethnicity, body mass index, weight gain during pregnancy, quality of glycemic control and insulin therapy. Discussion To our knowledge, this will be the first study to provide data on the prevalence of PS-UI and RAM and PFM physical and biomolecular muscle profiles after C-section in mothers with GDM. The longitudinal design allows for the assessment of cause-effect relationships between GDM, PS-UI, and PFMs and RAMs myopathy. The findings may reveal previously undetermined consequences of GDM.
    Type of Medium: Online Resource
    ISSN: 1471-2393
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2059869-5
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