Mechanobiological Mechanisms of Load-Induced Osteoarthritis in the Mouse Knee

Adebayo, Olufunmilayo O.; Holyoak, Derek T.; Meulen, Marjolein C. H. van der

doi:10.1115/1.4043970

Cited by 7 publications

(7 citation statements)

References 95 publications

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“…35 Intraarticular fracture models are also associated with alterations in mechanical stress within the joint as a result of changes in gait and presence of a fracture callus. 36,37 In contrast, tibial loading does not injure stabilizing tissues in the joint or change the gait of the loaded limb, 38,39 and changes in joint mechanics are limited to the development of osteophytes, which are thought to stabilize the joint rather than contribute to the progression of cartilage loss. 40,41 Although tibial loading changes joint structures, the apparent changes in joint biomechanics are not as severe as models that disrupt the joint capsule or fracture tissue.…”

Section: Discussionmentioning

confidence: 99%

Obesity and load‐induced posttraumatic osteoarthritis in the absence of fracture or surgical trauma

Luna

Guss

Vasquez-Bolanos

et al. 2020

Journal Orthopaedic Research

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Osteoarthritis is increasingly viewed as a heterogeneous disease with multiple phenotypic subgroups. Obesity enhances joint degeneration in mouse models of posttraumatic osteoarthritis (PTOA). Most models of PTOA involve damage to surrounding tissues caused by surgery/fracture; it is unclear if obesity enhances cartilage degeneration in the absence of surgery/fracture. We used a nonsurgical animal model of load-induced PTOA to determine the effect of obesity on cartilage degeneration 2 weeks after loading. Cartilage degeneration was caused by a single bout of cyclic tibial loading at either a high or moderate load magnitude in adult male mice with severe obesity (C57Bl6/J + high-fat diet), mild obesity (toll-like receptor 5 deficient mouse [TLR5KO]), or normal adiposity (C57Bl6/J mice + normal diet and TLR5KO mice in which obesity was prevented by manipulation of the gut microbiome). Two weeks after loading, cartilage degeneration occurred in limbs loaded at a high magnitude, as determined by OARSI scores (P < .001). However, the severity of cartilage damage did not differ among groups. Osteophyte width and synovitis of loaded limbs did not differ among groups. Furthermore, obesity did not enhance cartilage damage in limbs evaluated 6 weeks after loading. Constituents of the gut microbiota differed among groups. Our findings suggest that, in the absence of surgery/fracture, obesity may not influence cartilage loss after a single mechanical insult, suggesting that either damage to surrounding tissues or repeated mechanical insult is necessary for obesity to influence cartilage degeneration. These findings further illustrate heterogeneity in PTOA phenotypes and complex interactions between mechanical/metabolic factors in cartilage loss.

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Section: Discussionmentioning

confidence: 99%

Obesity and load‐induced posttraumatic osteoarthritis in the absence of fracture or surgical trauma

Luna

Guss

Vasquez-Bolanos

et al. 2020

Journal Orthopaedic Research

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“…5,62,[64][65][66] Rodent models are broadly used. 63, [67][68][69][70] Approaches to induce OA differ ( Figure 2). OA can be induced by direct damage of knee joint cartilage by application of monosodium iodoacetate (MIA model) or other harmful agents.…”

Section: In Vitro and In Vivo Disease Models For Elucidation Of Oa Thmentioning

confidence: 99%

“… 76 Novel models based on joint cartilage overloading by high impact or cyclic overloading (inducing non-invasively posttraumatic joint injury leading to posttraumatic OA [PTOA]) have also been proposed. 68 , 77 In addition, more specific models have been described such as creating surgically patellofemoral OA by shortening the patellar ligament and thereby, changing the position of the patella and hence, its fitting accuracy in the femoropatellar groove 78 or facet joint OA in the spine of rats. 79 Finally, estrogen-deprivation by ovariectomy is also used 62 to induce OA, being simultaneously a well-known model for osteoporosis.…”

Section: In Vitro and In Vivo Disease Models For Elucidation Of Oa Thmentioning

confidence: 99%

Experimental Therapeutics for the Treatment of Osteoarthritis

Schulze‐Tanzil

2021

JEP

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Osteoarthritis (OA) therapy remains a large challenge since no causative treatment options are so far available. Despite some main pathways contributing to OA are identified its pathogenesis is still rudimentary understood. A plethora of therapeutically promising agents are currently tested in experimental OA research to find an opportunity to reverse OA-associated joint damage and prevent its progression. Hence, this review aims to summarize novelly emerging experimental approaches for OA. Due to the diversity of strategies shown only main aspects could be summarized here including herbal medicines, nanoparticular compounds, growth factors, hormones, antibody-, cell-and extracellular vesicle (EV)-based approaches, optimized tools for joint viscosupplementation, genetic regulators such as si-or miRNAs and promising combinations. An abundant multitude of compounds obtained from plants, environmental, autologous or synthetic sources have been identified with anabolic, anti-inflammatory,-catabolic and anti-apoptotic properties. Some ubiquitous signaling pathways such as wingless and Integration site-1 (Wnt), Sirtuin, Tolllike receptor (TLR), mammalian target of rapamycin (mTOR), Nuclear Factor (NF)-κB and complement are involved in OA and addressed by them. Hyaluronan (HA) provided benefit in OA since many decades, and novel HA formulations have been developed now with higher HA content and long-term stability achieved by cross-linking suitable to be combined with other agents such as components from herbals or chemokines to attract regenerative cells. pH-or inflammation-sensitive nanoparticular compounds could serve as versatile slowrelease systems of active compounds, for example, miRNAs. Some light has been brought into the intimate regulatory network of small RNAs in the pathogenesis of OA which might be a novel avenue for OA therapy in future. Attraction of autologous regenerative cells by chemokines and exosome-based treatment strategies could also innovate OA therapy.

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“…To test our hypothesis, we induced OA pathology in wild type (WT, C57Bl/6) mice by applying cyclic compression (9.0N peak load, 1200 cycles, 4Hz frequency, 5 days/week) to the left tibiae of young (10-week-old) and adult (26-week-old) female mice. This loading regimen induces cartilage matrix damage, including proteoglycan loss, fibrillation, and erosion as well as osteophyte formation (7)(8)(9)(10). In all studies, the contralateral limbs served as the control.…”

Section: T Cells In Ipsilateral Lymph Nodes Increased With Cyclic Tibmentioning

confidence: 99%

T cells Mediate Progression of Load-Induced Osteoarthritis

Wheeler

Antoinette

Kim

et al. 2020

Preprint

Self Cite

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Osteoarthritis (OA) is a degenerative disease that manifests as joint damage and synovial inflammation. To date, most studies have focused on the decrease in cartilage stiffness, chondrocyte viability, and changes in matrix-degrading enzymes. With the exception of a few inflammatory cytokines and macrophages, the immune response in OA is poorly characterized, and the crosstalk of joint damage with T and B cells in local lymph nodes is unknown. Here, using an in vivo mouse model of mechanical loading of mouse tibia, we demonstrate that CD8+ T cells and subsets of CD4+ T cells, and not B cells, increase in the local lymph nodes and contribute to the progression of load-induced OA pathology. We demonstrate that T cell response is sex-and age-dependent. Mechanical loading of T cell knock-out mice that lack αβ T cell receptor carrying cells resulted in attenuation of both cartilage degradation and osteophyte formation in loaded joints, with a concomitant increase in γδ+ T cells. Restricting the migration of T cells in lymphoid tissues through the systemic treatment using Sphingosine-1-phosphate (S1P) inhibitor, decreased localization of T cells in synovium, and attenuated cartilage degradation. Our results lay the foundation of the role T cells play in the joint damage of load-induced OA and allude to the use of S1P inhibitors and T cell immunotherapies for slowing the progression of OA pathology.

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Mechanobiological Mechanisms of Load-Induced Osteoarthritis in the Mouse Knee

Cited by 7 publications

References 95 publications

Obesity and load‐induced posttraumatic osteoarthritis in the absence of fracture or surgical trauma

Obesity and load‐induced posttraumatic osteoarthritis in the absence of fracture or surgical trauma

Experimental Therapeutics for the Treatment of Osteoarthritis

T cells Mediate Progression of Load-Induced Osteoarthritis

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