Erin Teeple

Prevention of Cartilage Degeneration and Restoration of Chondroprotection by Lubricin Tribosupplementation in the Rat Following Anterior Cruciate Ligament Transection

OBJECTIVE To investigate whether cartilage degeneration is prevented or minimized following intraarticular injections of lubricin derived from human synoviocytes in culture, recombinant human PRG4 (rhPRG4), or human synovial fluid (SF) in a rat model of anterior cruciate ligament (ACL) injury. METHODS Unilateral ACL transection (ACLT) was performed in Lewis rats (n = 45). Nine animals were left untreated. The remaining rats were given intraarticular injections (50 microl/injection) of either phosphate buffered saline (PBS) (n = 9), human synoviocyte lubricin (200 microg/ml; n = 9), rhPRG4 (200 microg/ml; n = 9), or human SF lubricin (200 microg/ml; n = 9) twice weekly beginning on day 7 after injury. Joints were harvested on day 32 after injury. Histologic analysis was performed using Safranin O-fast green staining, and articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Histologic specimens were immunoprobed for lubricin and sulfated glycosaminoglycans. A 24-hour urine collection was performed on days 17 and 29 postinjury, and urinary C-terminal telopeptide of type II collagen (CTX-II) levels were measured. RESULTS Treatment with human synoviocyte lubricin resulted in significantly lower OARSI scores for cartilage degeneration compared with no treatment or PBS treatment (P < 0.05). Increased immunostaining for lubricin in the superficial zone chondrocytes and on the surface of cartilage was observed in lubricin-treated, but not untreated or PBS-treated, joints. On day 17, urinary CTX-II levels in human synoviocyte lubricin- and human SF lubricin-treated animals were significantly lower than those in untreated animals (P = 0.005 and P = 0.002, respectively) and in PBS-treated animals (P = 0.002 and P < 0.001, respectively). CONCLUSION After treatment with any of the 3 types of lubricin evaluated in this study, a reduction in cartilage damage following ACLT was evident, combined with a reduction in type II collagen degradation. Our findings indicate that intraarticular lubricin injection following an ACL injury may be beneficial in retarding the degeneration of cartilage and the development of posttraumatic OA.

Animal Models of Osteoarthritis: Challenges of Model Selection and Analysis

ABSTRACTOsteoarthritis (OA) is the most common musculoskeletal disease, affecting millions of individuals worldwide. New treatment approaches require an understanding of the pathophysiology of OA and its biomechanical, inflammatory, genetic, and environmental risk factors. The purpose of animal models of OA is to reproduce the pattern and progression of degenerative damage in a controlled fashion, so that opportunities to monitor and modulate symptoms and disease progression can be identified and new therapies developed. This review discusses the features, strengths, and weaknesses of the common animal models of OA; considerations to be taken when choosing a method for experimental induction of joint degeneration; and the challenges of measuring of OA progression and symptoms in these models.

Effects of Supplemental Intra-articular Lubricin and Hyaluronic Acid on the Progression of Posttraumatic Arthritis in the Anterior Cruciate Ligament–Deficient Rat Knee

Background: Lubricin and hyaluronic acid lubricate articular cartilage and prevent wear. Because lubricin loss occurs after anterior cruciate ligament injury, intra-articular lubricin injections may reduce cartilage damage in the anterior cruciate ligament–deficient knee. Purpose: This study was conducted to determine if lubricin and/or hyaluronic acid supplementation will reduce cartilage damage in the anterior cruciate ligament–deficient knee. Study Design: Controlled laboratory study. Methods: Thirty-six male rats, 3 months old, underwent unilateral anterior cruciate ligament transection. They were randomized to 4 treatments: (1) saline (phosphate-buffered saline [PBS]), (2) hyaluronic acid (HA), (3) purified human lubricin (LUB), and (4) LUB and HA (LUB+HA). Intra-articular injections were given twice weekly for 4 weeks starting 1 week after surgery. Knees were harvested 1 week after the final injection. Radiographs of each limb and synovial fluid lavages were obtained at harvest. Histologic analysis was performed to assess cartilage damage using safranin O/fast green staining. Radiographs were scored for the severity of joint degeneration using the modified Kellgren-Lawrence scale. Synovial fluid levels of sulfated glycosaminoglycan, collagen II breakdown, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and lubricin were measured using enzyme-linked immunosorbent assay (ELISA). Results: Treatment with LUB or LUB+HA significantly decreased radiographic and histologic scores of cartilage damage (P = .039 and P = .015, respectively) when compared with the PBS and HA conditions. There was no evidence of an effect of HA nor was the LUB effect HA-dependent, suggesting that the addition of HA did not further reduce damage. The synovial fluid of knees treated with LUB had significantly more lubricin in the synovial fluid at euthanasia, although there were no differences in the other cartilage metabolism biomarkers. Conclusion: Supplemental intra-articular LUB reduced cartilage damage in the anterior cruciate ligament–transected rat knee 6 weeks after injury, while treatment with HA did not. Clinical Relevance: Although longer term studies are needed, intra-articular supplementation (tribosupplementation) with lubricin after anterior cruciate ligament injury may protect the articular cartilage in the anterior cruciate ligament–injured knee.

Prevention of cartilage degeneration and gait asymmetry by lubricin tribosupplementation in the rat following anterior cruciate ligament transection.

OBJECTIVE To investigate whether cartilage degeneration is prevented or minimized in a rat model of anterior cruciate ligament (ACL) injury following a single dose-escalated intraarticular injection of lubricin derived from human synoviocytes in culture. METHODS Unilateral ACL transection (ACLT) of the right hind limb was performed in Lewis rats (n = 56). Control animals underwent a capsulotomy alone, leaving the ACL intact (n = 11). Intraarticular injections (50 μl/injection) of phosphate buffered saline (PBS; n = 14 rats) and human synoviocyte lubricin (1,600 μg/ml; n = 14 rats) were performed on day 7 postsurgery. Animals were killed on day 70 postsurgery. Histologic specimens were immunoprobed for lubricin and sulfated glycosaminoglycans. Urinary C-telopeptide of type II collagen (CTX-II) levels were measured on days 35 and 70 postsurgery. Hind limb maximum applied force was determined using a variable resistor walkway to monitor quadruped gait asymmetries. RESULTS Increased immunostaining for lubricin in the superficial zone and on the surface of cartilage was observed in lubricin-treated and control animals but not in PBS-treated or untreated animals with ACLT. On days 35 and 70 after surgery, urinary CTX-II levels in human synoviocyte lubricin-treated animals were lower than in untreated and PBS-treated animals (P < 0.005 and P < 0.001, respectively). Animals with ACLT treated with human synoviocyte lubricin and control animals distributed their weight equally between hind limbs compared to PBS-treated or untreated animals (P < 0.01). CONCLUSION Our findings indicate that a single intraarticular injection of concentrated lubricin following ACLT reduces type II collagen degradation and improves weight bearing in the affected rat joint. These findings support the practice of tribosupplementation with lubricin for retarding cartilage degeneration and possibly the development of posttraumatic osteoarthritis.

Comparison of differential biomarkers of osteoarthritis with and without posttraumatic injury in the Hartley guinea pig model

The objective was to compare biomarkers of articular cartilage metabolism in synovial fluid from Hartley guinea pig knees, with and without anterior cruciate ligament transection (ACLT), to establish whether detectable differences in biomarker levels exist between primary and secondary osteoarthritis (OA). Synovial fluid lavages and knees were obtained from 3‐month (control group) and 12‐month (primary OA group) animals. Another group of animals (posttraumatic OA group) underwent unilateral ACLT at 3 months, and samples were obtained 9 months postsurgery. Synovial fluid concentrations of stromal cell‐derived‐factor (SDF‐1), collagen fragments (C2C), proteoglycan (GAG), lubricin, matrix metalloproteinase‐13 (MMP‐13), and Interleukin‐1 (IL‐1β) were evaluated. Cartilage damage was assessed via histology. The highest concentrations of C2C and SDF‐1 in synovial fluid were found in the posttraumatic OA group, moderate concentrations were found in the primary OA group, and low concentrations in the control group. GAG release in synovial fluid was similar to C2C and SDF‐1. The lubricin concentrations were significantly lower in ACLT joints than either the control or 12‐month primary OA groups, but not between the control and primary OA groups. Higher levels of MMP‐13 and IL‐1β were detected in the joints of the posttraumatic OA group as compared to the control or primary OA groups. Histology revealed greatest OA damage in the posttraumatic OA group, followed by moderate and minimal damage in primary OA and control groups, respectively. This study indicates that the biomarkers and progression of OA may differ in the Hartley guinea pig models with and without posttraumatic OA.

Intra-articular Recombinant Human Proteoglycan 4 Mitigates Cartilage Damage After Destabilization of the Medial Meniscus in the Yucatan Minipig.

Background: Lubricin, or proteoglycan 4 (PRG4), is a glycoprotein responsible for joint boundary lubrication. PRG4 has been shown previously to be down-regulated after traumatic joint injury such as a meniscal tear. Preliminary evidence suggests that intra-articular injection of PRG4 after injury will reduce cartilage damage in rat models of surgically induced posttraumatic osteoarthritis. Objective: To determine the efficacy of intra-articular injection of full-length recombinant human lubricin (rhPRG4) for reducing cartilage damage after medial meniscal destabilization (DMM) in a preclinical large animal model. Study Design: Controlled laboratory study. Methods: Unilateral DMM was performed in 29 Yucatan minipigs. One week after DMM, animals received 3 weekly intra-articular injections (3 mL per injection): (1) rhPRG4 (1.3 mg/mL; n = 10); (2) rhPRG4+hyaluronan (1.3 mg/mL rhPRG4 and 3 mg/mL hyaluronan [~950 kDA]; n = 10); and (3) phosphate-buffered saline (PBS; n = 9). Hindlimbs were harvested 26 weeks after surgery. Cartilage integrity was evaluated by use of macroscopic (India ink) and microscopic (safranin O–fast green and hematoxylin and eosin) scoring systems. Secondary outcomes evaluated via enzyme-linked immunosorbent assay (ELISA) included PRG4 levels in synovial fluid, carboxy-terminal telepeptide of type II collagen (CTX-II) concentrations in urine and serum, and interleukin 1β (IL-1β) levels in synovial fluid and serum. Results: The rhPRG4 group had significantly less macroscopic cartilage damage in the medial tibial plateau compared with the PBS group (P = .002). No difference was found between the rhPRG4+hyaluronan and PBS groups (P = .23). However, no differences in microscopic damage scores were observed between the 3 groups (P = .70). PRG4 production was elevated in the rhPRG4 group synovial fluid compared with the PBS group (P = .033). The rhPRG4 group presented significantly lower urinary CTX-II levels, but not serum levels, when compared with the PBS (P = .013) and rhPRG4+hyaluronan (P = .011) groups. In serum and synovial fluid, both rhPRG4 (P = .006; P = .017) and rhPRG4+hyaluronan groups (P = .009; P = .03) presented decreased IL-1β levels. Conclusion: All groups exhibited significant cartilage degeneration after DMM surgery. However, animals treated with rhPRG4 had the least amount of cartilage damage and less inflammation, providing evidence that intra-articular injections of rhPRG4 may slow the progression of posttraumatic osteoarthritis. Clinical Relevance: Patients with meniscal trauma are at high risk for posttraumatic osteoarthritis. This study demonstrates that an intra-articular injection regimen of rhPRG4 may attenuate cartilage damage after meniscal injury.

Lifting and exertion injuries decrease after implementation of an integrated hospital-wide safe patient handling and mobilisation programme

Objective With increasing emphasis on early and frequent mobilisation of patients in acute care, safe patient handling and mobilisation practices need to be integrated into these quality initiatives. We completed a programme evaluation of a safe patient handling and mobilisation programme within the context of a hospital-wide patient care improvement initiative that utilised a systems approach and integrated safe patient equipment and practices into patient care plans. Methods Baseline and 12-month follow-up surveys of 1832 direct patient care workers assessed work practices and self-reported pain while an integrated employee payroll and injury database provided recordable injury rates collected concurrently at 2 hospitals: the study hospital with the programme and a comparison hospital. Results Safe and unsafe patient handling practice scales at the study hospital improved significantly (p<0.0001 and p=0.0031, respectively), with no differences observed at the comparison hospital. We observed significant decreases in recordable neck and shoulder (Relative Risk (RR)=0.68, 95% CI 0.46 to 1.00), lifting and exertion (RR=0.73, 95% CI 0.60 to 0.89) and pain and inflammation (RR=0.78, 95% CI 0.62 to 1.00) injury rates at the study hospital. Changes in rates at the comparison hospital were not statistically significant. Conclusions Within the context of a patient mobilisation initiative, a safe patient handling and mobilisation programme was associated with improved work practices and a reduction in recordable worker injuries. This study demonstrates the potential impact of utilising a systems approach based on recommended best practices, including integration of these practices into the patients plan for care.

Arthroscopic irrigation of the bovine stifle joint increases cartilage surface friction and decreases superficial zone lubricin

The purpose of this study was to determine the effects of arthroscopic irrigation on cartilage superficial zone lubricin and surface friction. Arthroscopic partial meniscectomy is one of the most commonly performed orthopedic surgeries in the United States, but rates of osteoarthritis progression following this procedure are high. The effect of arthroscopic irrigation on articular surface lubrication has not been previously considered as a contributing factor in outcomes after arthroscopy. Fourteen bovine stifle joints were randomized to receive arthroscopic irrigation (n=7) or no treatment (n=7). Full-thickness osteochondral explants from these joints underwent friction testing to measure static and dynamic coefficients of friction. Following mechanical testing, samples were fixed and stained for lubricin. Percent integrated density, a measure of the amount of lubricin in the superficial zone (0-100µm depth), was determined. Static and dynamic coefficients of friction were found to be significantly greater in arthroscopy specimens compared to controls (p=0.02 and p<0.001, respectively). Percent integrated density of lubricin in the superficial zone was significantly lower in arthroscopy specimens compared to controls (p<0.001).

Pendulum mass affects the measurement of articular friction coefficient.

Friction measurements of articular cartilage are important to determine the relative tribologic contributions made by synovial fluid or cartilage, and to assess the efficacy of therapies for preventing the development of post-traumatic osteoarthritis. Stantons equation is the most frequently used formula for estimating the whole joint friction coefficient (μ) of an articular pendulum, and assumes pendulum energy loss through a mass-independent mechanism. This study examines if articular pendulum energy loss is indeed mass independent, and compares Stantons model to an alternative model, which incorporates viscous damping, for calculating μ. Ten loads (25-100% body weight) were applied in a random order to an articular pendulum using the knees of adult male Hartley guinea pigs (n=4) as the fulcrum. Motion of the decaying pendulum was recorded and μ was estimated using two models: Stantons equation, and an exponential decay function incorporating a viscous damping coefficient. μ estimates decreased as mass increased for both models. Exponential decay model fit error values were 82% less than the Stanton model. These results indicate that μ decreases with increasing mass, and that an exponential decay model provides a better fit for articular pendulum data at all mass values. In conclusion, inter-study comparisons of articular pendulum μ values should not be made without recognizing the loads used, as μ values are mass dependent.

Outcomes of safe patient handling and mobilization programs: A meta-analysis

BACKGROUND Variability in patient care settings and the range of patient handling tasks present challenges in developing and evaluating safe patient handling and mobilization (SPHM) programs. OBJECTIVE We performed a systematic meta-analysis of SPHM program evaluations. METHODS Systematic literature review identified published SPHM program evaluations. Injury Rate Ratios (IRR), pre- to post-intervention, were used to estimate intervention effects and to examine the influence of patient care level, program components, and follow-up time using meta-regression. RESULTS 27 articles reported evaluations from 44 sites. Combined effect estimate for all SPHM programs was 0.44 (95% CI 0.36, 0.54), reflecting substantial injury reductions after program implementation. While specific program components were not associated with greater effectiveness, longer follow-up duration was associated with greater injury rate reduction (p = 0.01) and intervention effects varied by level of care (p = 0.01), with the greatest effect in intensive care unit interventions (IRR 0.14; 95% CI 0.07, 0.30). CONCLUSIONS SPHM programs appear to be highly effective in reducing injuries. More research is needed to identify the most effective interventions for different patient care levels.