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Posttraumatic arthritis (PTA) occurs commonly after articular fracture and may arise, in part, from joint surface incongruity after injury. MRL/MpJ (MRL) "super-healer" mice are protected from PTA compared to C57BL/6 (B6) mice following articular fracture. However, the relationship between the initial displacement of the articular surface, biologic response, and susceptibility to PTA after fracture remains unclear. The objective of this study was to assess whether joint incongruity after articular fracture, as measured by in vivo micro-computed tomography (microCT), could predict pathomechanisms of PTA in mice. B6 and MRL mice (n = 12/strain) received a closed articular fracture (fx) of the left tibial plateau. Articular incongruity was quantified as bone surface deviations (BSD) for each in vivo microCT scan obtained from pre-fx to 8 weeks post-fx, followed by histologic assessment of arthritis. Serum concentrations of bone formation (PINP) and bone resorption (CTX-I) biomarkers were quantified longitudinally. Both strains showed increases in surface incongruity over time, as measured by increases in BSD. In B6 mice, acute surface incongruity was significantly correlated to the severity of PTA (R 2  = 0.988; p = .0006), but not in MRL mice (R 2  = 0.224; p = .220). PINP concentrations significantly decreased immediately post-fx in B6 mice (p = .023) but not in MRL mice, indicating higher bone synthesis in MRL mice. MRL/MpJ mice demonstrate a unique biologic response to articular fracture such that the observed articular bone surface displacement does not correlate with the severity of subsequent PTA. Clinical Relevance: Identifying therapies to enhance acute biologic repair following articular fracture may mitigate the risk of articular surface displacement for PTA., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

The inflammatory response to joint injury, specifically intra-articular fracture, has been implicated in posttraumatic arthritis development. However, the role of T cells in regulating the development of posttraumatic arthritis is unclear. We hypothesized that the absence of T cells would lead to less severe posttraumatic arthritis following intra-articular fracture. T cell-deficient, athymic nude, and wild-type C57BL/6NJ mice were assessed at 8 weeks following closed articular fracture. Joints were assessed using histologic scores of arthritis, synovitis, and bone morphology via micro computed tomography. Cells were profiled in whole blood via flow cytometry, and plasma and synovial fluid derived cytokines were quantified by multiplex analysis. Compared to C57BL/6NJ mice, nude mice had significantly greater histologic evidence of arthritis and synovitis. Whole blood immune cell profiling revealed a lower percentage of dendritic cells but increased natural killer (NK) cells in nude mice. Concurrently, nude mice had significantly higher levels of NK cells in synovial tissue. Concentrations of plasma interleukin 1β (IL-1β) and tumor necrosis factor α, and synovial fluid IL-12, IL-17, and IL-6 in both knees were greater in nude mice. Outcomes of this study suggest that T cells may play a protective regulatory role against the development of posttraumatic arthritis. Clinical significance: Lack of functional T cells exacerbated the development of posttraumatic arthritis following intra-articular fracture suggesting that critical regulators of the immune responses, contained within the T cell population, are required for protection. Future research identifying the specific T cell subsets responsible for modulating disease immunopathogenesis will lead to new therapeutic targets to mitigate posttraumatic arthritis., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

The purpose of this work is to determine the relationship between biomarkers of inflammation, structure, and pain with radiographic disc space narrowing (DSN) in community-based participants. A total of 74 participants (37 cases and 37 controls) enrolled in the Johnston County Osteoarthritis Project during 2006-2010 were selected. The cases had at least mild radiographic DSN and low back pain (LBP). The controls had neither radiographic evidence of DSN nor LBP. The measured analytes from human serum included N-cadherin, Keratin-19, Lumican, CXCL6, RANTES, IL-17, IL-6, BDNF, OPG, and NPY. A standard dolorimeter measured pressure-pain threshold. The coefficients of variation were used to evaluate inter- and intra-assay reliability. Participants with similar biomarker profiles were grouped together using cluster analysis. The binomial regression models were used to estimate risk ratios (RR) and 95% confidence intervals (CI) in propensity score-matched models. Significant associations were found between radiographic DSN and OPG (RR = 3.90; 95% CI: 1.83, 8.31), IL-6 (RR = 2.54; 95% CI: 1.92, 3.36), and NPY (RR = 2.06 95% CI: 1.62, 2.63). Relative to a cluster with low levels of biomarkers, a cluster representing elevated levels of OPG, RANTES, Lumican, Keratin-19, and NPY (RR = 3.04; 95% CI: 1.22, 7.54) and a cluster representing elevated levels of NPY (RR = 2.91; 95% CI: 1.15, 7.39) were significantly associated with radiographic DSN. Clinical Significance: These findings suggest that individual and combinations of biochemical biomarkers may reflect radiographic DSN. This is just one step toward understanding the relationships between biochemical biomarkers and DSN that may lead to improved intervention delivery. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1027-1037, 2020., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with post-traumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post-traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL-1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25-fold) versus 3 days post-fracture in MRL/MpJ mice (15-fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL-1α-stimulated total MMP activity (p = 0.09) and S-GAG (p = 0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1220-1227, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Anterior cruciate ligament (ACL) injuries are common and lead to posttraumatic osteoarthritis (PTOA) in a high percentage of patients. Research has been ineffective in identifying successful treatment options for people suffering from symptomatic PTOA resulting in a shift of focus toward the young, ACL injured patients at risk of developing PTOA. Randomized clinical trials examining the very early phase after ACL injury are ideal to study this population; however, these trials face significant challenges regarding recruitment as well as reproducibility of patient-reported outcomes (PROs) and inflammatory and/or chondrodegenerative biomarkers associated with early PTOA. The aim of this work was to develop an approach to allow for early recruitment into an RCT for early treatment following ACL injury and to analyze the variability of commonly used measures and biomarkers at various time points after injury. This paper reports the study design and data related to the first month of treatment for the placebo group of an ongoing 2-year clinical trial to evaluate the effect of an early intra-articular intervention after ACL injury. The results of this study suggest that acute ACL injury results in early changes of both inflammatory and chondrodegenerative biomarkers. These results also provide vital information for researchers to consider when developing future protocols, both related to the logistics of early patient enrollment as well as the appropriate timing of biomarker and patient-reported outcome collection. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:641-650, 2017., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Methods for the detection of the temporal and spatial generation of painful symptoms are needed to improve the diagnosis and treatment of painful neuropathies and to aid preclinical screening of molecular therapeutics., Methods: In this study, we utilized in vivo luminescent imaging of NF-κB activity and serum cytokine measures to investigate relationships between the NF-κB regulatory network and the presentation of painful symptoms in a model of neuropathy., Results: The chronic constriction injury model led to temporal increases in NF-κB activity that were strongly and non-linearly correlated with the presentation of pain sensitivities (i.e. mechanical allodynia and thermal hyperalgesia). The delivery of NEMO-binding domain peptide reduced pain sensitivities through the inhibition of NF-κB activity in a manner consistent with the demonstrated non-linear relationship. Importantly, the combination of non-invasive measures of NF-κB activity and NF-κB-regulated serum cytokines produced a highly predictive model of both mechanical (R(2) = 0.86) and thermal (R(2) = 0.76) pain centred on the NF-κB regulatory network (NF-κB, IL-6, CXCL1)., Conclusions: Using in vivo luminescent imaging of NF-κB activity and serum cytokine measures, this work establishes NF-κB and NF-κB-regulated cytokines as novel multivariate biomarkers of pain-related sensitivity in this model of neuropathy that may be useful for the rapid screening of novel molecular therapeutics., (© 2015 European Pain Federation - EFIC®)

An estimated 12% of patients seeking surgical intervention for symptomatic arthritis have an etiology of post-traumatic arthritis (PTA). The onset of PTA is rapid in the setting of articular fracture (AF). The investigation began with development of a murine model of a closed AF that develops PTA. In the process of characterizing this model a technique was developed for assessing quantitative synovial fluid biomarker concentrations. The work began with observations of the natural history of PTA development in the C57BL/6 strain of mice. A species of mice (MRL/MpJ) was found that is protected from PTA after AF. Further work identified key differences between mouse strains that did and did not develop PTA. This knowledge led to an intervention based on anti-cytokine (interleukin 1 receptor antagonist, (IL-1Ra) delivery in the C57BL/6 strain of mice that successfully prevented PTA following AF. This success in preventing PTA in the murine model has elucidated several important clinical implications: 1) Pro-inflammatory cytokines play an important role in the development of PTA after joint injury, 2) Pharmacologic intervention can lessen the severity of PTA after an AF, and 3) The murine AF model of joint injury provides a novel means of studying mechanisms of PTA development., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objective: The inflammatory response following an articular fracture is thought to play a role in the development of posttraumatic arthritis (PTA) but has not been well characterized. The objective of this study was to characterize the acute inflammatory response, both locally and systemically, in joint synovium, synovial fluid (SF), and serum following articular fracture of the ankle. We hypothesized that intraarticular fracture would alter the synovial environment and lead to increased local and systemic inflammation., Methods: Synovial tissue biopsy specimens, SF samples, and serum samples were collected from patients with an acute articular ankle fracture (n = 6). Additional samples (normal, ankle osteoarthritis [OA], and knee OA [n = 6 per group]) were included for comparative analyses. Synovial tissue was assessed for synovitis and macrophage count. SF and serum were assessed for cytokines (interferon-γ [IFNγ], interleukin-1β [IL-1β], IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor α) and chemokines (eotaxin, eotaxin 3, IFNγ-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], MCP-4, macrophage-derived chemokine, macrophage inflammatory protein 1β, and thymus and activation-regulated chemokine)., Results: Synovitis scores were significantly higher in ankle fracture tissue compared with normal ankle tissue (P = 0.007), and there was a trend toward an increased abundance of CD68+ macrophages in ankle fracture synovium compared with normal knee synovium (P = 0.06). The concentrations of all cytokines and chemokines were elevated in the SF of patients with ankle fracture compared with those in SF from OA patients with no history of trauma. Only the concentration of IL-6 was significantly increased in the serum of patients with ankle fracture compared with normal serum (P = 0.027)., Conclusion: Articular fracture of the ankle increased acute local inflammation, as indicated by increased synovitis, increased macrophage infiltration into synovial tissue, and increased SF concentrations of biomarkers of inflammation. Characterizing the acute response to articular fracture provides insight into the healing process and may help to identify patients who may be at greater risk of PTA., (© 2015, American College of Rheumatology.)

Objective: To evaluate joint tissue remodeling using the urinary collagen biomarkers urinary α-C-telopeptide of type I collagen (α-CTX) and urinary C-telopeptide of type II collagen (CTX-II) and to determine the association of these biomarkers with osteoarthritis (OA) severity, progression, and localized knee bone turnover., Methods: Participants (n = 149) with symptomatic and radiographic knee OA underwent fixed-flexion knee radiography at baseline and 3 years, and late-phase bone scintigraphy of both knees at baseline, which were scored semiquantitatively for osteophyte and joint space narrowing (JSN) severity and uptake intensity, with scores summed across knees. Urinary concentrations of α-CTX and CTX-II were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis of human OA knees was performed to localize the joint tissue origin of the biomarker epitopes., Results: Urinary α-CTX concentrations correlated strongly with the intensity of bone scintigraphic uptake and with JSN progression (risk ratio 13.2) and osteophyte progression (risk ratio 3). Urinary CTX-II concentrations were strongly associated with intensity of bone scintigraphic uptake, with JSN and osteophyte severity, and with OA progression based on osteophyte score. Urinary α-CTX localized primarily to high bone turnover areas in subchondral bone. CTX-II localized to the bone-cartilage interface, the tidemark, and damaged articular cartilage., Conclusion: Baseline urinary α-CTX, which was localized to high turnover areas of subchondral bone, was associated with dynamic bone turnover of knees, as signified by scintigraphy, and progression of both osteophytes and JSN. Urinary CTX-II correlated with JSN and osteophyte severity and progression of osteophytes. To our knowledge, this represents the first report of serologic markers reflecting subchondral bone turnover. These collagen markers may be useful for noninvasive detection and quantification of active subchondral bone turnover and joint remodeling in knee OA., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To investigate the relationship between NF-κB activity, cytokine levels, and pain sensitivities in a rodent model of osteoarthritis (OA)., Methods: OA was induced in transgenic NF-κB-luciferase reporter mice via intraarticular injection of monosodium iodoacetate (MIA). Using luminescence imaging we evaluated the temporal kinetics of NF-κB activity and its relationship to the development of pain sensitivities and serum cytokine levels in this model., Results: MIA induced a transient increase in joint-related NF-κB activity at early time points (day 3 after injection) and an associated biphasic pain response (mechanical allodynia). NF-κB activity, serum interleukin-6 (IL-6), IL-1β, and IL-10 levels accounted for ∼75% of the variability in pain-related mechanical sensitivities in this model. Specifically, NF-κB activity was strongly correlated with mechanical allodynia and serum IL-6 levels in the inflammatory pain phase of this model (day 3), while serum IL-1β was strongly correlated with pain sensitivities in the chronic pain phase of the model (day 28)., Conclusion: Our findings suggest that NF-κB activity, IL-6, and IL-1β may play distinct roles in pain sensitivity development in this model of arthritis and may distinguish the acute pain phase from the chronic pain phase. This study establishes luminescence imaging of NF-κB activity as a novel imaging biomarker of pain sensitivities in this model of OA., (Copyright © 2014 by the American College of Rheumatology.)