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The objective of this study was to assess the prognostic potential of magnetic resonance (MR)-detected meniscal degeneration in relation to incident destabilizing meniscal tears (radial, complex, root, or macerated) or accelerated knee osteoarthritis (AKOA). We used existing MR data from a case-control study of three groups from the Osteoarthritis Initiative without radiographic KOA at baseline: AKOA, typical KOA, and no KOA. From these groups, we included people without medial and lateral meniscal tear at baseline (n = 226) and 48-month meniscal data (n = 221). Intermediate-weighted fat-suppressed MR images annually from baseline to the 48-month visit were graded using a semiquantitative meniscal tear classification criterion. Incident destabilizing meniscal tear was defined as progressing from an intact meniscus to a destabilizing tear by the 48-month visit. We used two logistic regression models to assess whether: (1) presence of medial meniscal degeneration was associated with an incident medial destabilizing meniscal tear, and (2) presence of meniscal degeneration in either meniscus was associated with incident AKOA over the next 4 years. People with the presence of a medial meniscal degeneration had three times the odds of developing an incident destabilizing medial meniscal tear within 4 years compared with a person without medial meniscus degeneration (odds ratio [OR]: 3.03; 95% confidence interval [CI]: 1.40-6.59). People with meniscal degeneration had five times the odds of developing incident AKOA within 4 years compared with a person without meniscal degeneration in either meniscus (OR: 5.04; 95% CI: 2.57-9.89). Meniscal degeneration on MR is clinically meaningful as it relates to future poor outcomes., (© 2023 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Encapsulation of median nerves is a hallmark of overuse-induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG-3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever-pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti-CCN2 monoclonal antibody (HRHF-Rest/FG-3019) or IgG (HRHF-Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF-untreated and HRHF-Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3-immunopositive nuclei in ventral horn neurons in HRHF-untreated rats, compared with controls (which showed none). FG-3019-treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3-immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti-CCN2 treatment reverses these effects., (© 2020 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

We assessed whether adding magnetic resonance (MR)-based features to a base model of clinically accessible participant characteristics (i.e., serological, radiographic, demographic, symptoms, and physical function) improved classification of adults who developed accelerated radiographic knee osteoarthritis (AKOA) or not over the subsequent 4 years. We conducted a case-control study using radiographs from baseline and the first four annual visits of the osteoarthritis initiative to define groups. Eligible individuals had no radiographic KOA in either knee at baseline (Kellgren-Lawrence [KL] grade <2). We classified two groups matched on sex (i) AKOA: at least one knee developed advanced-stage KOA (KL = 3 or 4) within 48 months and (ii) did not develop AKOA within 48 months. The MR-based features were assessments of bone, effusion/synovitis, tendons, ligaments, cartilage, and menisci. All characteristics and MR-based features were from the baseline visit. Classification and regression tree analyses were performed to determine classification rules and identify statistically important variables. The CART models with and without MR features each explained approximately 40% of the variability. Adding MR-based features to the model yielded modest improvements in specificity (0.90 vs. 0.82) but lower sensitivity (0.62 vs. 0.70) than the base model. There was consistent evidence that serum glucose, effusion-synovitis volume, and cruciate ligament degeneration are statistically important variables in classifying individuals who will develop AKOA. We found common MR-based measures failed to dramatically improve classification. These findings also show a complex interplay among participant characteristics and a need to identify novel characteristics to improve classification. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2420-2428, 2019., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Fibrosis may be a key factor in sensorimotor dysfunction in patients with chronic overuse-induced musculoskeletal disorders. Using a clinically relevant rodent model, in which performance of a high demand handle-pulling task induces tissue fibrosis and sensorimotor declines, we pharmacologically blocked cellular communication network factor 2 (CCN2; connective tissue growth factor) with the goal of reducing the progression of these changes. Young adult, female Sprague-Dawley rats were shaped to learn to pull at high force levels (10 min/day, 5 weeks), before performing a high repetition high force (HRHF) task for 3 weeks (2 h/day, 3 days/week). HRHF rats were untreated, or treated in task weeks 2 and 3 with a monoclonal antibody that blocks CCN2 (FG-3019), or a control immunoglobulin G (IgG). Control rats were untreated or received FG-3019, IgG, or vehicle (saline) injections. Mean task reach rate and grasp force were higher in 3-week HRHF + FG-3019 rats, compared with untreated HRHF rats. Grip strength declined while forepaw mechanical sensitivity increased in untreated HRHF rats, compared with controls; changes improved by FG-3019 treatment. The HRHF task increased collagen in multiple tissues (flexor digitorum muscles, nerves, and forepaw dermis), which was reduced with FG-3019 treatment. FG-3019 treatment also reduced HRHF-induced increases in CCN2 and transforming growth factor β in muscles. In tendons, FG-3019 reduced HRHF-induced increases in CCN2, epitendon thickening, and cell proliferation. Our findings indicate that CCN2 is critical to the progression of chronic overuse-induced multi-tissue fibrosis and functional declines. FG-3019 treatment may be a novel therapeutic strategy for overuse-induced musculoskeletal disorders. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2004-2018, 2019., (© 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.)

Objective: To determine whether accelerated knee osteoarthritis (KOA) is preceded by, and characterized over time by, destabilizing meniscal tears or other pathologic changes., Methods: We selected 3 sex-matched groups of subjects from the first 48 months of the Osteoarthritis Initiative, comprising adults who had a knee without KOA (Kellgren/Lawrence [K/L] radiographic grade <2) at baseline. Subjects in the accelerated KOA group developed KOA of K/L grade ≥3, those with typical KOA showed increased K/L radiographic scores, and those with no KOA had the same K/L grade over time. An index visit was the visit when the radiographic criteria for accelerated KOA and typical KOA were met (the no KOA group was matched to the accelerated KOA group). The observation period was up to 2 years before and after an index visit. Radiologists reviewed magnetic resonance (MR) images of the index knee and identified destabilizing meniscal tears (root tears, radial tears, complex tears), miscellaneous pathologic features (acute ligamentous or tendinous injuries, attrition, subchondral insufficiency fractures, other incidental findings), and meniscal damage in >2 of 6 regions (3 regions per meniscus: anterior horn, body, posterior horn). In addition, bone marrow lesions (BMLs) and cartilage damage on MR images were quantified. Linear mixed regression models were performed to analyze the results., Results: At 1 year before the index visit, >75% of adults with accelerated KOA had meniscal damage in ≥2 regions (odds ratio 3.19 [95% confidence interval 1.70-5.97] versus adults with typical KOA). By the index visit, meniscal damage in ≥2 regions was ubiquitous in adults with accelerated KOA, including 42% of subjects having evidence of a destabilizing meniscal tear (versus 14% of subjects with typical KOA). These changes corresponded to findings of larger BMLs and greater cartilage loss in the accelerated KOA group., Conclusion: Accelerated KOA is characterized by destabilizing meniscal tears in a knee compromised by meniscal damage in >2 regions, and also characterized by the presence of large BMLs and greater cartilage loss., (© 2018, American College of Rheumatology.)

We assessed which combinations of risk factors can classify adults who develop accelerated knee osteoarthritis (KOA) or not and which factors are most important. We conducted a case-control study using data from baseline and the first four annual visits of the Osteoarthritis Initiative. Participants had no radiographic KOA at baseline (Kellgren-Lawrence [KL]<2). We classified three groups (matched on sex): (i) accelerated KOA: >1 knee developed advance-stage KOA (KL = 3 or 4) within 48 months; (ii) typical KOA: >1 knee increased in radiographic scoring (excluding those with accelerated KOA); and (iii) No KOA: no change in KL grade by 48 months. We selected eight predictors: Serum concentrations for C-reactive protein, glycated serum protein (GSP), and glucose; age; sex; body mass index; coronal tibial slope, and femorotibial alignment. We performed a classification and regression tree (CART) analysis to determine rules for classifying individuals as accelerated KOA or not (no KOA and typical KOA). The most important baseline variables for classifying individuals with incident accelerated KOA (in order of importance) were age, glucose concentrations, BMI, and static alignment. Individuals <63.5 years were likely not to develop accelerated KOA, except when overweight. Individuals >63.5 years were more likely to develop accelerated KOA except when their glucose levels were >81.98 mg/dl and they did not have varus malalignment. The unexplained variance of the CART = 69%. These analyses highlight the complex interactions among four risk factors that may classify individuals who will develop accelerated KOA but more research is needed to uncover novel risk factors. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:876-880, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

We aimed to determine if serum measures of impaired glucose homeostasis (glucose concentrations or glycated serum protein, GSP) or systemic inflammation (high-sensitivity C-reactive protein, CRP) are related to incident typical knee osteoarthritis (KOA) or incident accelerated KOA. We conducted a case-control study using the Osteoarthritis Initiative's baseline and first four annual visits. All participants had no radiographic KOA at baseline (Kellgren-Lawrence [KL] < 2). We classified three groups: (i) incident accelerated KOA: >1 knee developed advance-stage KOA (KL Grade 3 or 4) within 48 months; (ii) incident typical KOA: > 1 knee increased in radiographic scoring within 48 months (excluding those with accelerated KOA); and (iii) No KOA: no change in KL grade by 48 months. We matched on sex. A laboratory blinded to group assignment used baseline serum samples to conduct assays for CRP, GSP, and glucose. Due to nonlinear relationships, we used three piece-wise multinomial logistic regression models to determine if baseline CRP, GSP, or glucose were associated with incident typical KOA or accelerated KOA compared with no KOA. We adjusted for age, body mass index, and sex. We analyzed 54 adults/group. Lower and higher GSP concentrations were associated with incident typical KOA compared with adults with concentrations (log) closer to 5.7 (lnGSp < 5.7: OR = 0.28, 95%CI = 0.08-0.93; lnGSp > 5.7: OR = 3.21, 95%CI = 1.07-9.62). Glucose, GSP, and CRP were not significantly associated with incident accelerated KOA. Glucose homeostasis may predict individuals at risk of incident typical KOA but not accelerated KOA, which may indicate accelerated KOA is a distinct disorder from typical KOA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2282-2287, 2017., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The purpose of this study was to determine whether an association existed between self-reported symptom and function scores and tissue turnover or inflammatory biomarker changes after a running bout among individuals with and without an acute knee-injury history. A pre-test/post-test prospective cohort study design (Level II) of 22 participants was conducted. Eleven physically active individuals with a history of anterior cruciate ligament surgery and/or meniscus surgery within 4 years of study participation were matched to 11 healthy control participants. All participants completed self-reported outcome measures (Knee Osteoarthritis Outcomes Score and Tegner activity level) assessing knee symptoms and functional levels prior to the run. Blood samples were taken both pre- and post-30-minute run at a prescribed pace on a treadmill to determine serum biomarker concentration changes. Tegner activity levels were inversely related to type II collagen/type II collagen synthesis marker ratio biomarker changes after the run (r = -0.45, p = 0.01). Quality-of-life scores pre-exercise were inversely related to interleukin-1β changes after the run (r = -0.50, p = 0.02). No other correlation coefficients were statistically significant (r = -0.39 to 0.36). Ultimately, individuals with lower activity and quality-of-life scores experienced greater increases in collagen turnover and inflammation after a running bout, respectively. A gradual increase in activity (e.g., frequency, duration, intensity) may be warranted in this group prior to returning to activities that involve running. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:612-617, 2017., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Recently, diabetes has been linked to rotator cuff disease and adhesive capsulitis, conditions with increased stiffness and inflammation. Unfortunately, limited research exists examining how hyperglycemia affects the native shoulder (tendon and capsule) properties. Therefore, the objectives of this study were to compare shoulder joint mechanics, tendon properties (mechanics and immunohistochemistry), and capsule of healthy control and hyperglycemic rats 8 weeks following induction of hyperglycemia with a submaximal dose of streptozotocin (STZ). Eighteen rats were injected with STZ to induce hyperglycemia or citrate buffer (control) and underwent normal cage activity for 8 weeks. Passive joint mechanics demonstrated significantly less external rotation in the hyperglycemic group compared to controls, with no other group differences. Tendon mechanical properties (stiffness and modulus) were not significantly different between groups at both the insertion site and mid-substance. Immunohistochemistry staining of the tendon and capsule demonstrated significantly increased interleukin 1-beta (IL1-β) and advanced glycated end-products (AGE) staining localized to the insertion and mid-substance of the tendon but not the capsule. In addition, tumor necrosis factor alpha (TNF-α) staining was significantly increased in the superior capsule but not the supraspinatus tendon. This study demonstrates that isolated hypergylcemia does not diminish shoulder mechanical properties but does induce a chronic inflammatory response., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Myelomeningocele (MMC) is a common congenital malformation and the most severe form of spina bifida characterized by the protrusion of spinal cord and meninges through the spinal defect. Our objective was to improve the assessment of congenital vertebral defects in animal models of MMC using three-dimensional high resolution micro-computed tomography (micro-CT) imaging and quantitative digital analyses methods., Methods: Lumbosacral MMC was induced in fetal rats by exposure of pregnant mothers at embryonic day 10 (E10) to all-trans retinoic acid, and rats were examined at term (embryonic day 22). The axial skeleton was examined in an MMC model for the first time using ex vivo micro-CT at 10 μm voxel resolution to allow high resolution two-dimensional and three-dimensional characterization of anomalies in lumbosacral vertebrae, and quantitative assessment of distances between dorsal vertebral arches in lumbosacral regions in MMC rats, compared with normal controls., Results: We observed, in detail, skeletal defects in lumbosacral vertebra of MMC rats, including in the morphology of individual dorsal vertebral arches. Use of high resolution micro-CT has also enabled us to identify the delayed (nonfused) or absent ossification in vertebral bodies, increased fusion of adjacent lateral vertebral elements, and quantify the extent of dorsal arch widening. Distances between dorsal vertebral arches showed statistically significant increases from L5 through S4 in MMC rats, compared with normal controls., Conclusion: High-resolution micro-CT combined with digital quantification methods is a powerful technique ideally suited for precise assessment of complex congenital skeletal abnormalities such as examined in this rodent model of MMC., (© 2014 Wiley Periodicals, Inc.)

Background: Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted., Results: We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-β-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype., Conclusions: We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation., (Copyright © 2012 Wiley Periodicals, Inc.)

Upper extremity tendinopathies are associated with performance of forceful repetitive tasks. We used our rat model of repetitive strain injury to study changes induced in forelimb flexor digitorum tendons. Rats were trained to perform a high repetition high force (HRHF) handle-pulling task (12 reaches/min at 60 +/- 5% maximum pulling force [MPF]), or a low repetition negligible force (LRNF) reaching and food retrieval task (three reaches/min at 5 +/- 5% MPF), for 2 h/day in 30 min sessions, 3 days/week for 3-12 weeks. Forelimb grip strength was tested. Flexor digitorum tendons were examined at midtendon at the level of the carpal tunnel for interleukin (IL)-1beta, neutrophil, and macrophage influx, Substance P, connective tissue growth factor (CTGF), and periostin-like factor (PLF) immunoexpression, and histopathological changes. In HRHF rats, grip strength progressively decreased, while IL-1beta levels progressively increased in the flexor digitorum peritendon (para- and epitendon combined) and endotendon with task performance. Macrophage invasion was evident in week 6 and 12 HRHF peritendon but not endotendon. Also in HRHF rats, Substance P immunoexpression increased in week 12 peritendon as did CTGF- and PLF-immunopositive fibroblasts, the increased fibroblasts contributing greatly to peritendon thickening. Endotendon collagen disorganization was evident in week 12 HRHF tendons. LRNF tendons did not differ from controls, even at 12 weeks. Thus, we observed exposure-dependent changes in flexor digitorum tendons within the carpal tunnel, including increased inflammation, nociceptor-related neuropeptide immunoexpression, and fibrotic histopathology, changes associated with grip strength decline.

We investigated inflammation in rats performing a low repetition, negligible force (LRNF) or high repetition, negligible force (HRNF) task of reaching and retrieving food pellets at target rates of two or four reaches/min for 2 h/day, for 6-8 weeks. Serum was assayed for 11 cytokines and chemokines; forelimb tissues for four cytokines. Macrophages were counted in forelimb tissues of LRNF rats to add to results from our previous studies of HRNF rats. In HRNF rats, serum IL-1 alpha, IL-1 beta, TNFalpha, MIP2, MIP3a, and RANTES were elevated in weeks 6 and 8. In contrast, only MIP2 and MIP3a increased in serum of LRNF rats. In 8 week HRNF reach limb tissues, IL-1 alpha, IL-1beta, TNFalpha, and IL-10 increased in distal bones, IL-1 alpha and -beta in muscles, and TNFalpha in tendons. Only IL-10 increased in LRNF reach limb muscles in week 8. Serum IL-1 alpha and MIP2 correlated with macrophages in LRNF loose connective tissues, serum MIP3a and MIP2 correlated negatively with grip strength, while serum TNFalpha, MIP3a, and MIP2 correlated positively with total number of reaches. Thus, several tissue and circulating cytokines/chemokines increase in an exposure dependent manner following short-term performance of repetitive reaching tasks and correlate with macrophage infiltration and decreasing grip strength., ((c) 2008 Orthopaedic Research Society.)

This study investigated changes in motor skills and tissues of the upper extremity (UE) with regard to injury and inflammatory reactions resulting from performance of a voluntary forelimb repetitive reaching and grasping task in rats. Rats reached for food at a rate of 4 reaches/min, 2 h/day, and 3 days/week for up to 8 weeks during which reach rate, task duration and movement strategies were observed. UE tissues were collected bilaterally at weekly time points of 3-8 weeks and examined for morphological changes. Serum was tested for levels of interleukin-1alpha (IL-1) protein. The macrophage-specific antibody, ED1, was used to identify infiltrating macrophages and the ED2 antibody was used to identify resident macrophages. Rats were unable to maintain baseline reach rate in weeks 5 and 6 of task performance. Alternative patterns of movement emerged. Fraying of tendon fibrils was observed after 6 weeks in the mid-forelimb. After 4 weeks, a general elevation of ED1-IR macrophages were seen in all tissues examined bilaterally including the contralateral, uninvolved forelimb and hindlimbs. Significantly more resident macrophages were seen at 6 and 8 weeks in the reach limb. At 8 weeks, serum levels of IL-1alpha increased significantly above week 0. Our results demonstrate that performance of repetitive tasks elicits motor decrements, signs of injury and a cellular and tissue responses associated with inflammation.