Kinematics of meniscal‐ and ACL‐transected mouse knees during controlled tibial compressive loading captured using roentgen stereophotogrammetry

Adebayo, Olufunmilayo O.; Ko, Frank C.; Goldring, Steven R.; Goldring, Mary B.; Wright, Timothy M.; Meulen, Marjolein C. H. van der

doi:10.1002/jor.23285

Cited by 17 publications

(25 citation statements)

References 53 publications

(129 reference statements)

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“…Using a peak load of 9N for 1200 cycles, this model induced controlled instabilities in the knee joint 31 , and recapitulated OA pathology in the cartilage and SCB after 1, 2, and 6 weeks of daily loading in adult C57BL/6 mice 27,28 . A single bout of loading also induced disease initiation and progression, demonstrating that OA pathology in this model can be initiated by cell-mediated processes that are activated by mechanical loading 32 .…”

Section: Introductionmentioning

confidence: 79%

Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice

Adebayo

Park

et al. 2017

Osteoarthritis and Cartilage

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Objective Animal models recapitulating post-traumatic osteoarthritis (OA) suggest that subchondral bone (SCB) properties and remodeling may play major roles in disease initiation and progression. Thus, we investigated the role of SCB properties and its effects on load-induced OA progression by applying a tibial loading model on two distinct mouse strains treated with alendronate (ALN). Design Cyclic compression was applied to the left tibia of 26-week-old male C57Bl/6 (B6, low bone mass) and FVB (high bone mass) mice. Mice were treated with ALN (26μg/kg/day) or vehicle (VEH) for loading durations of 1, 2, or 6 weeks. Changes in articular cartilage and subchondral and epiphyseal cancellous bone were analyzed using histology and microcomputed tomography. Results FVB mice exhibited thicker cartilage, a thicker SCB plate, and higher epiphyseal cancellous bone mass and tissue mineral density than B6 mice. Loading induced cartilage pathology, osteophyte formation, and SCB changes; however, lower initial SCB mass and stiffness in B6 mice did not attenuate load-induced OA severity compared to FVB mice. In contrast, FVB mice exhibited less cartilage damage, and slower-growing and less mature osteophytes. In B6 mice, inhibiting bone remodeling via ALN treatment exacerbated cartilage pathology after 6 weeks of loading, while in FVB mice, inhibiting bone remodeling protected limbs from load-induced cartilage loss. Conclusions Intrinsically lower SCB properties were not associated with attenuated load-induced cartilage loss. However, inhibiting bone remodeling produced differential patterns of OA pathology in animals with low compared to high SCB properties, indicating that these factors do influence load-induced OA progression.

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Section: Introductionmentioning

confidence: 79%

Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice

Adebayo

Park

et al. 2017

Osteoarthritis and Cartilage

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“…Another reason may be that the relative short period of time between injury and assessment of cartilage destruction in this model precludes the development of loading induced cartilage damage, at least during the 12-week monitoring period post-injury. Recent mechanical loading studies revealed few kinematic changes in DMM joints (33). Future studies will determine how long Phlpp inhibitor treatment is effective and if inhibitors block the initiation of cartilage damage and/or promote regeneration after the onset of cartilage degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Recent mechanical loading studies revealed few kinematic changes in DMM joints. 33 Future studies will determine how long Phlpp inhibitor treatment is effective and if inhibitors block the initiation of cartilage damage and/or promote regeneration after the onset of cartilage degeneration.…”

Section: Discussionmentioning

confidence: 99%

Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis

Hwang

Feigenson

Begun

et al. 2017

Journal Orthopaedic Research

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Phlpp protein phosphatases are abnormally abundant within human osteoarthritic articular chondrocytes and may contribute to the development of osteoarthritis. Mice lacking Phlpp1 were previously shown to be resistant to post-traumatic osteoarthritis. Here a small molecule with therapeutic properties that inhibits Phlpp1 and Phlpp2 was tested for its ability to slow post-traumatic OA in mice and to stimulate anabolic pathways in human articular cartilage from OA joints. PTOA was induced in male C57Bl/6 mice by surgically destabilizing the meniscus. Seven weeks after surgery, mice received a single intra-articular injection of the Phlpp inhibitor NSC117079 or saline. Mechanical allodynia was measured with von Frey assays, mobility was tracked in an open field system, and cartilage damage was assessed histologically. A single intra-articular injection of the Phlpp inhibitor NSC117079 attenuated mechanical allodynia and slowed articular cartilage degradation in joints with a destabilized meniscus. Animals treated with the Phlpp inhibitor 7 weeks after injury maintained normal activity levels, while those in the control group traveled shorter distances and were less active 3 months after the joint injury. NSC117079 also increased production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from OA patients and increased phosphorylation of Phlpp1 substrates (AKT2, ERK1/2, and PKC) in human articular chondrocytes. Our results indicate that Phlpp inhibitor NSC117079 is a novel osteoarthritis disease modifying drug candidate that may have palliative affects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1487-1497, 2018.

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“…To understand the relationship between joint mechanics and the ensuing biological response, a number of in vitro and in vivo models have emerged. In vivo animal models and in vitro tissue explant models have demonstrated that increased joint translation, contact stress, and impact force can lead to cartilage degeneration . In vivo patient‐based studies of joint kinematics and tissue contact have also suggested that changed kinematics during walking can influence changes in joint morphology .…”

Section: Discussionmentioning

confidence: 99%

“…In vivo animal models and in vitro tissue explant models have demonstrated that increased joint translation, contact stress, and impact force can lead to cartilage degeneration. 8,[27][28][29][30] In vivo patient-based studies of joint kinematics and tissue contact have also suggested that changed kinematics during walking can influence changes in joint morphology. 31 Conceptually, a deeper understanding of a patient's joint mechanics and how those mechanics are affected by injury, could be used to assess the risk of joint tissue degeneration after meniscal injury, and hence the need to surgically intervene.…”

Section: Discussionmentioning

confidence: 99%

Reducing uncertainty when using knee‐specific finite element models by assessing the effect of input parameters

Guo

Santner

Lerner

et al. 2017

Journal Orthopaedic Research

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Little is known about knee-specific factors that influence contact mechanics. Finite Element (FE) models offer a powerful tool to study contact mechanics, but there often exists ambiguity in the exact values of the inputs (tissue properties, for example), which can result in a range of output values. Our objective was to quantify the reduction in the range of output values (defined herein as “uncertainty”) from FE models of the human knee joint when known pre-defined values are used for clinically measurable inputs. To achieve this goal, we applied a statistically-augmented FE approach to three human cadaveric knees for which full geometric and kinematic data were available. Two sets of conditions were simulated: All model inputs, clinically measurable or not, were varied to represent a ‘normal’ patient population (Condition 1); subsets of clinically measurable variable inputs were fixed at specific values (called patient derived inputs, or PDIs) while the other variables were varied over ‘normal’ values (Condition 2). We found that by fixing body mass index and the anterior-posterior position of the meniscal-bony insertion points, model output uncertainty was reduced by one- to three-fifths. The magnitude of uncertainty reduction was strongly influenced by the individual knee. It was observed that knees with great anterior-posterior translation during gait had greater reductions in uncertainty when PDIs were used. This study represents the first step in developing FE models of the human knee joint based on inputs that can be derived from patients in a clinical setting.

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Kinematics of meniscal‐ and ACL‐transected mouse knees during controlled tibial compressive loading captured using roentgen stereophotogrammetry

Cited by 17 publications

References 53 publications

Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice

Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice

Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis

Reducing uncertainty when using knee‐specific finite element models by assessing the effect of input parameters

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