Severe obesity increased load-induced cartilage damage, while milder changes in adiposity/metabolic syndrome seen in TLR5KO mice did not. Furthermore, the effects of systemic inflammation/obesity on cartilage damage depend on the duration of mechanical loading. Lastly, reduced cartilage damage in the TLR5KOΔMicrobiota mice suggests that the gut microbiome may influence cartilage pathology.

Osteoarthritis (OA) is a progressive, degenerative disease of articulating joints that not only affects the elderly, but also involves younger, more active individuals with prolonged participation in high physical-demand activities. Thus, effective therapies that are easy to adopt clinically are critical in limiting the societal burden associated with OA. This review is focused on intra-articular injectable regimens and provides a comprehensive look at existing in vivo models of OA that might be suitable for developing, testing, and finding a cure for OA by intra-articular injections. We first discuss the pathology, molecular mechanisms responsible for the initiation and progression of OA, and challenges associated with disease-specific targeting of OA. We proceed to discuss available animal models of OA and provide a detailed perspective on the use of mouse models in studies of experimental OA. We finally provide a closer look at intra-articular injectable treatments for OA, focusing on biomaterials-based nanoparticles, and provide a comprehensive overview of the various nanometer-size ranges studied.

Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates. To test our hypotheses, we applied cyclic compression to the left tibiae of 6-month-old cho/+ male mice and wild-type (WT) littermates for 1, 2, and 6 weeks at moderate (4.5 N) and high (9.0 N) peak load magnitudes. We then characterized load-induced cartilage and bone changes by histology, microcomputed tomography, and immunohistochemistry. Prior to loading, cho/+ mice had less dense, thinner cortical bone compared to WT littermates. In addition, in loaded and non-loaded limbs, cho/+ mice had thicker cartilage. With high loads, cho/+ mice experienced less load-induced cartilage damage at all time points and displayed decreased matrix metalloproteinase (MMP)-13 levels compared to WT littermates. The thinner, less dense cortical bone and thicker cartilage were unexpected and may have contributed to the reduced severity of load-induced cartilage damage in cho/+ mice. Furthermore, the spontaneous proteoglycan loss resulting from the mutant collagen XI was not additive to cartilage damage from mechanical loading, suggesting that these risk factors act through independent pathways. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:711-720, 2018.

Osteoarthritis (OA) of the knee joint is a degenerative disease initiated by mechanical stress that affects millions of individuals. The disease manifests as joint damage and synovial inflammation. Post-traumatic osteoarthritis (PTOA) is a specific form of OA caused by mechanical trauma to the joint. The progression of PTOA is prevented by immediate post-injury therapeutic intervention. Intra-articular injection of anti-inflammatory therapeutics (e.g. corticosteroids) is a common treatment option for OA before end-stage surgical intervention. However, the efficacy of intra-articular injection is limited due to poor drug retention time in the joint space and the variable efficacy of corticosteroids. Here, we endeavored to characterize a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system as a ‘mechanical pillow’ to cushion the load-bearing joint, withstand repetitive loading and improve the efficacy of intra-articular injections of nanoparticles containing dexamethasone, an anti-inflammatory agent. PEG-4MAL hydrogels maintained their mechanical properties after physiologically relevant cyclic compression and released therapeutic payload in an on-demand manner under in vitro inflammatory conditions. Importantly, the on-demand hydrogels did not release nanoparticles under repetitive mechanical loading as experienced by daily walking. Although dexamethasone had minimal protective effects on OA-like pathology in our studies, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from cartilage degradation and inhibit osteophyte formation in an in vivo load-induced OA mouse model.

Objective: Mechanical loading and joint health have a unique relationship in osteoarthritis (OA) onset and progression. Although high load levels adversely affect cartilage health, exercise that involves low to moderate load levels can alleviate OA symptoms. We sought to isolate the beneficial effects of mechanical loading using controlled in vivo cyclic tibial compression. We hypothesized that low-level cyclic compression would attenuate post-traumatic OA symptoms induced by destabilization of the medial meniscus (DMM). Methods: 10-week-old C57Bl/6J male mice underwent DMM surgery (n ¼ 51). After a 5-day postoperative recovery period, we applied daily cyclic tibial compression to the operated limbs at low (1.0N or 2.0N) or moderate (4.5N) magnitudes for 2 or 6 weeks. At the completion of loading, we compared cartilage and peri-articular bone features of mice that underwent DMM and loading to mice that only underwent DMM. Results: Compared to DMM alone, low-level cyclic compression for 6 weeks attenuated DMM-induced cartilage degradation (OARSI score, P ¼ 0.008, 95% confidence interval (CI): 0.093 to 0.949). Low-level loading attenuated DMM-induced osteophyte formation after 2 weeks (osteophyte size, P ¼ 0.033, 95% CI: 3.27e114.45 mm), and moderate loading attenuated subchondral bone sclerosis after 6 weeks (tissue mineral density (TMD), P ¼ 0.011, 95% CI: 6.32e70.60 mg HA/ccm) compared to limbs that only underwent DMM. Finally, loading had subtle beneficial effects on cartilage cellularity and aggrecanase activity after DMM. Conclusion: Low-level cyclic compression is beneficial to joint health after an injury. Therefore, the progression of early OA may be attenuated by applying well controlled, low-level loading shortly following joint trauma.