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Background: Several tissues contribute to the onset and advancement of knee osteoarthritis (OA). One tissue type that is worthy of closer evaluation, particularly in the context of sex, is the infrapatellar fat pad (IFP). We previously demonstrated that removal of the IFP had short-term beneficial effects for a cohort of male Dunkin-Hartley guinea pigs. The present project was designed to elucidate the influence of IFP removal in females of this OA-prone strain. It was hypothesized that resection of the IFP would reduce the development of OA in knees of a rodent model predisposed to the disease., Methods: Female guinea pigs (n=16) were acquired at an age of 2.5 months. Surgical removal of the IFP and associated synovium complex (IFP/SC) was executed at 3 months of age. One knee had the IFP/SC resected; a comparable sham surgery was performed on the contralateral knee. All animals were subjected to voluntary enclosure monitoring and dynamic weight-bearing, as well as compulsory treadmill-based gait analysis monthly; baseline data was collected prior to surgery. Guinea pigs were euthanized at 7 months. Knees from eight animals were evaluated via histology, mRNA expression, and immunohistochemistry (IHC); knees from the remaining eight animals were allocated to microcomputed tomography (microCT), biomechanical analyses (whole joint testing and indentation relaxation testing), and atomic absorption spectroscopy (AAS)., Results: Fibrous connective tissue (FCT) replaced the IFP/SC. Mobility/gait data indicated that unilateral IFP/SC removal did not affect bilateral hindlimb movement. MicroCT demonstrated that osteophytes were not a significant feature of OA in this sex; however, trabecular thickness (TbTh) in medial femorae decreased in knees containing the FCT. Histopathology scores were predominantly influenced by changes in the lateral tibia, which demonstrated that histologic signs of OA were increased in knees containing the native IFP/SC versus those with the FCT. Similarly, indentation testing demonstrated higher instantaneous and equilibrium moduli in the lateral tibial articular cartilage of control knees with native IFPs. AAS of multiple tissue types associated with the knee revealed that zinc was the major trace element influenced by removal of the IFP/SC., Conclusions: Our data suggest that the IFP/SC is a significant component driving knee OA in female guinea pigs and that resection of this tissue prior to disease has short-term benefits. Specifically, the formation of the FCT in place of the native tissue resulted in decreased cartilage-related OA changes, as demonstrated by reduced Osteoarthritis Research Society International (OARSI) histology scores, as well as changes in transcript, protein, and cartilage indentation analyses. Importantly, this model provides evidence that sex needs to be considered when investigating responses and associated mechanisms seen with this intervention., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1886/coif). The authors have no conflicts of interest to declare., (2024 Annals of Translational Medicine. All rights reserved.)

Background: The infrapatellar fat pad (IFP) is the largest adipose deposit in the knee; however, its contributions to the homeostasis of this organ remain undefined. To determine the influence of the IFP and its associated synovium (IFP/synovium complex or IFP/SC) on joint health, this study evaluated the progression of osteoarthritis (OA) following excision of this unit in a rodent model of naturally-occurring disease., Methods: Male Dunkin-Hartley guinea pigs (n=18) received surgical removal of the IFP in one knee at 3 months of age; contralateral knees received sham surgery as matched internal controls. Mobility and gait assessments were performed prior to IFP/SC removal and monthly thereafter. Animals were harvested at 7 months of age. Ten set of these knees were processed for microcomputed tomography (microCT), histopathology, transcript expression analyses, and immunohistochemistry (IHC); 8 sets of knees were dedicated to microCT and biomechanical testing (material properties of knee joints tissues and anterior drawer laxity)., Results: Fibrous connective tissue (FCT) developed in place of the native adipose depot. Gait demonstrated no significant differences between IFP/SC removal and contralateral hindlimbs. MicroCT OA scores were improved in knees containing the FCT. Quantitatively, IFP/SC-containing knees had more osteophyte development and increased trabecular volume bone mineral density (vBMD) in femora and tibiae. Histopathology confirmed maintenance of articular cartilage structure, proteoglycan content, and chondrocyte cellularity in FCT-containing knees. Transcript analyses revealed decreased expression of adipose-related molecules and select inflammatory mediators in FCTs compared to IFP/SCs. This was verified via IHC for two key inflammatory agents. The medial articular cartilage in knees with native IFP/SCs showed an increase in equilibrium modulus, which correlated with increased amounts of magnesium and phosphorus., Discussion/conclusion: Formation of the FCT resulted in reduced OA-associated changes in both bone and cartilage. This benefit may be associated with: a decrease in inflammatory mediators at transcript and protein levels; and/or improved biomechanical properties. Thus, the IFP/SC may play a role in the pathogenesis of knee OA in this strain, with removal prior to disease onset appearing to have short-term benefits., (© 2022. The Author(s).)

Post-traumatic osteoarthritis (PTOA) is a debilitating disease that is a result of a breakdown of knee joint tissues following traumatic impact. The interplay of how these tissues influence each other has received little attention because of complex interactions. This study was designed to correlate the degeneration of the menisci, cartilage and subchondral bone following an acute traumatic event that resulted in anterior cruciate ligament (ACL) and medial meniscus tears. We used a well-defined impact injury animal model that ruptures the ACL and tears the menisci. Subsequently, the knee joints underwent ACL reconstruction and morphological analyses were performed on the menisci, cartilage and subchondral bone at 1-, 3- and 6-months following injury. The results showed that the morphological scores of the medial and lateral menisci worsened with time, as did the tibial plateau and femoral condyle articular cartilage scores. The medial meniscus was significantly correlated to the medial tibial subchondral bone at 1 month ( p = 0.01), and to the medial tibial cartilage at 3 months ( p = 0.04). There was only one significant correlation in the lateral hemijoint, i.e., the lateral tibial cartilage to the lateral tibial subchondral bone at 6 months ( p = 0.05). These data may suggest that, following trauma, the observed medial meniscal damage should be treated acutely by means other than a full or partial meniscectomy, since that procedure may have been the primary cause of degenerative changes in the underlying cartilage and subchondral bone. In addition to potentially treating meniscal damage differently, improvements could be made in optimizing treatment of acute knee trauma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Haut Donahue, Narez, Powers, Dejardin, Wei and Haut.)

Background: Meniscal root tears cause menisci and their insertions to inadequately distribute loads and potentially leave underlying articular cartilage unprotected. Untreated meniscal root tears are becoming increasingly recognized to induce joint degradation; however, little information is known about anterior meniscal root tears and how they affect joint tissue., Purpose: To observe the early degenerative changes within the synovial fluid, menisci, tibial articular cartilage, and subchondral bone after arthroscopic creation of untreated anterior meniscal root tears., Study Design: Controlled laboratory study., Methods: Anterolateral meniscal root tears were created in 1 knee joint of 5 adult Flemish Giant rabbits, and anteromedial meniscal root tears were created in 4 additional rabbits. The contralateral limbs were used as nonoperated controls. The animals were euthanized at 8 weeks postoperatively; synovial fluid was aspirated, and tissue samples of menisci and tibial articular cartilage were collected and processed for multiple analyses to detect signs of early degeneration., Results: Significant changes were found within the synovial fluid, meniscal tissue, and tibial subchondral bone of the knees with anterior meniscal root tears when compared with controls. There were no significant changes identified in the tibial articular cartilage when comparing the tear groups with controls., Conclusion: This study demonstrated early degenerative changes within the synovial fluid, menisci, and tibial subchondral bone when leaving anterior meniscal root tears untreated for 8 weeks. The results suggest that meniscal tissue presents measurable, degenerative changes prior to changes within the articular cartilage after anterior meniscal root tears. Anterior destabilization of the meniscus arthroscopically may lead to measurable degenerative changes and be useful for future in vivo natural history and animal repair studies., Clinical Relevance: The present study is the first to investigate various tissue changes after anterior meniscal root tears of both the medial and lateral menisci. The results from this study suggest that degenerative changes occur within the synovial fluid, meniscus, and tibial subchondral bone prior to any measurable changes to the tibial articular cartilage. Further studies should expand on this study to evaluate how these components continue to progress when left untreated for long periods., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: R.F.L. receives royalties from Arthrex, Ossur, and Smith & Nephew; is a paid consultant for Arthrex, Ossur, and Smith & Nephew; and receives research support from Arthrex, Smith & Nephew, Ossur, and Linvatec. Funding for this project was provided by the Steadman Philippon Research Institute in Vail, Colorado.

Objective: The objective of this study was to monitor the progression of joint damage in two animal models of knee joint trauma using two non-invasive, clinically available imaging modalities., Methods: A 3-T clinical magnet and micro-computed tomography (μCT) was used to document changes immediately following injury (acute) and post-injury (chronic) at time points of 4, 8, or 12 weeks. Joint damage was recorded at dissection and compared to the chronic magnetic resonance imaging (MRI) record. Fifteen Flemish Giant rabbits were subjected to a single tibiofemoral compressive impact (ACLF), and 18 underwent a combination of anterior cruciate ligament (ACL) and meniscal transection (mACLT)., Results: All ACLF animals experienced ACL rupture, and 13 also experienced acute meniscal damage. All ACLF and mACLT animals showed meniscal and articular cartilage damages at dissection. Meniscal damage was documented as early as 4 weeks and worsened in 87% of the ACLF animals and 71% of the mACLT animals. Acute cartilage damage also developed further and increased in occurrence with time in both models. A progressive decrease in bone quantity and quality was documented in both models. The MRI data closely aligned with dissection notes suggesting this clinical tool may be a non-invasive method for documenting joint damage in lapine models of knee joint trauma., Conclusions: The study investigates the acute to chronic progression of meniscal and cartilage damage at various time points, and chronic changes to the underlying bone in two models of posttraumatic osteoarthritis (PTOA), and highlights the dependency of the model on the location, type, and progression of damage over time., (Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: Bighorn sheep (Ovis canadensis) routinely experience violent impacts to the head as part of intraspecific fighting. Dynamic 3D finite element models of the skull and horns of a male bighorn sheep were developed to gain an understanding of the roles that the horn and bone materials and structure play in absorbing the impact that occurs during ramming. The geometry and volume mesh of the model were derived from CT scan images. The models included the horn, bony horn core, and bone of the skull. The horn core fills a portion of the hollow horn and consists of a thin cortical bone shell filled with foam-like trabecular bone. Two modified models were also created: one with the distal half of the horn length removed to assess the effects of the tapered spiral geometry of the horn, and one with the internal trabecular bone material of the horn core removed. The trabecular bone material stored three times more strain energy during impact than the horn material in the intact model. Removing half of the horn length had the effect of increasing translational accelerations in the brain cavity by 49%. Removing the trabecular bone in the horn core resulted in a 442% increase in rotational accelerations within the brain cavity. These findings support the investigation of novel bioinspired materials and designs that could be used in mitigating brain injuries and in other applications involving high-impact collisions., Statement of Significance: Bighorn sheep routinely experience violent impacts to the head and horns without apparent negative consequences to the brain or horns. A portion of the horn is filled with a thin cortical bone shell containing foam-like trabecular bone. We developed novel dynamic finite element models of the skull and horns of bighorn sheep to gain an understanding of the roles that the horn and bone materials play in absorbing the impact that occurs during ramming. The study revealed that both horn and bone materials and the structures made from these materials (i.e., tapered spiral horns and foam-like trabecular bone struts) are important for absorbing impact energy and reducing brain cavity accelerations., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Traumatic impaction is known to cause acute cell death and macroscopic damage to cartilage and menisci in vitro. The purpose of this study was to investigate cell viability and macroscopic damage of the medial and lateral menisci using an in situ model of traumatic loading. Furthermore, the release of nitric oxide from meniscus, synovium, cartilage, and subchondral bone was also documented., Methods: The left limbs of five rabbits were subjected to tibiofemoral impaction resulting in anterior cruciate ligament (ACL) rupture and meniscal damage. Meniscal tear morphology was assessed immediately after trauma and cell viability of the lateral and medial menisci was assessed 24 hrs post-injury. Nitric oxide (NO) released from joint tissues to the media was assayed at 12 and 24 hrs post injury., Results: ACL and meniscal tearing resulted from the traumatic closed joint impact. A significant decrease in cell viability was observed in the lateral menisci following traumatic impaction compared to the medial menisci and control limbs. While NO release was greater in the impacted joints, this difference was not statistically significant., Conclusion: This is the first study to investigate acute meniscal viability following an in situ traumatic loading event that results in rupture of the ACL. The change in cell viability of the lateral menisci may play a role in the advancement of joint degeneration following traumatic knee joint injury.

Background: Damage to the knee meniscus may result in tears that are difficult or unable to heal, and are often treated by partial removal of the damaged tissue. In vitro, 20% dynamic compressive strains on meniscal tissue explants have resulted in an increase in the release of sulfated glycosaminoglycans (GAG) and nitric oxide (NO) from the tissue explants and increased expression of matrix metalloproteinases (MMP) and interleukin-1α (IL-1α). The objective of this study was to explore the efficacy of IL-1 blockade on the expression of a wide range of genes, as well as NO and GAG release, following dynamic compression of porcine meniscal explants., Methods: Explants were dynamically compressed for 2 h at 1 Hz to 0, 10, or 20% strain with and without a pre-treatment of 500 ng/ml interleukin-1 receptor antagonist (IL-1RA). Relative changes in gene expression of IL-1α, MMP-1, -3, -13, A Disintegrin and Metalloproteinase with ThromboSpondin 4 (ADAMTS-4), ADAMTS-5, iNOS, aggrecan, and COX-2, as well as changes in NO and GAG release, were measured with standard biochemical assays., Results: Expression of IL-1α, MMP-3, MMP-13, and ADAMTS-4 in superficial explants was significantly downregulated at 20% dynamic strain compared to 10% strain following treatment with IL-1RA. GAG and NO release were not significantly influenced by IL-1RA treatment., Conclusions: Treatment of meniscal explants with IL-1RA inhibited the expression of many catabolic genes following a single bout of high dynamic strain. IL-1RA may therefore be a potential therapy option during the acute phase of meniscal tear or meniscectomy treatment.

Objective: Following partial meniscectomy, the remaining meniscus is exposed to an altered loading environment. In vitro 20% dynamic compressive strains on meniscal tissue explants has been shown to lead to an increase in release of glycosaminoglycans from the tissue and increased expression of interleukin-1alpha (IL-1alpha). The goal of this study was to determine if compressive loading which induces endogenously expressed IL-1 results in downstream changes in gene expression of anabolic and catabolic molecules in meniscal tissue, such as MMP expression., Method: Relative changes in gene expression of MMP-1, MMP-3, MMP-9, MMP-13, A Disintegrin and Metalloproteinase with ThromboSpondin 4 (ADAMTS4), ADAMTS5, TNFalpha, TGFbeta, COX-2, Type I collagen (COL-1) and aggrecan and subsequent changes in the concentration of prostaglandin E(2) released by meniscal tissue in response to varying levels of dynamic compression (0%, 10%, and 20%) were measured. Porcine meniscal explants were dynamically compressed for 2h at 1Hz., Results: 20% dynamic compressive strains upregulated MMP-1, MMP-3, MMP-13 and ADAMTS4 compared to no dynamic loading. Aggrecan, COX-2, and ADAMTS5 gene expression were upregulated under 10% strain compared to no dynamic loading while COL-1, TIMP-1, and TGFbeta gene expression were not dependent on the magnitude of loading., Conclusion: This data suggests that changes in mechanical loading of the knee joint meniscus from 10% to 20% dynamic strain can increase the catabolic activity of the meniscus.

Objective: Partial meniscectomy is known to cause osteoarthritis (OA) of the underlying cartilage as well as alter the load on the remaining meniscus. Removal of 30-60% of the medial meniscus increases compressive strains from a maximum of approximately 10% to almost 20%. The goal of this study is to determine if meniscal cells produce catabolic molecules in response to the altered loading that results from a partial meniscectomy., Method: Relative changes in gene expression of interleukin-1 (IL-1), inducible nitric oxide synthase (iNOS) and subsequent changes in the concentration of nitric oxide (NO) released by meniscal tissue in response to compression were measured. Porcine meniscal explants were dynamically compressed for 2 h at 1 Hz to simulate physiological stimulation at either 10% strain or 0.05 MPa stress. Additional explants were pathologically stimulated to either 0% strain, 20% strain or, 0.1 MPa stress., Results: iNOS and IL-1 gene expression and NO release into the surrounding media were increased at 20% compressive strain compared to other conditions. Pathological unloading (0% compressive strain) of meniscal explants did not significantly change expression of IL-1 or iNOS genes, but did result in an increased amount of NO released compared to physiological strain of 10%., Conclusion: These data suggest that meniscectomies which reduce the surface area of the meniscus by 30-60% will increase the catabolic activity of the meniscus which may contribute to the progression of OA.

Fibrochondrocytes within meniscal tissue have been shown to alter their biochemical activity in response to changes in their mechanical environment. Meniscal tissue is known to contain both spherical (chondrocytic-like) and elliptical (fibroblastic-like) cells. We hypothesize that a cell's mechanical environment is governed by local material properties of the tissue around the cell, the cell morphology and the cell's position within the tissue. A two-dimensional, non-linear, fiber (collagen) reinforced, multi-scale, finite element model was utilized to quantify changes in the stress, strain, fluid velocity and fluid flow induced shear stress (FFISS) within and around fibrochondrocytes. Cells differing in morphology and size were modeled at different locations within an explant 6mm in diameter and 5mm thick, under 5% unconfined compression. Cellular stresses were an order of magnitude less than surrounding extracellular matrix stresses but cellular strains were higher. Cell size affected both the stress and strain levels within the cell, with smaller cells being exposed to smaller principal stresses and strains than larger cells of the same shape. The pericellular matrix of an elliptical cell was less effective at shielding the cell from large principal strains and stresses. FFISS were largest around small circular cells ( approximately 0.13Pa), and were dramatically affected by the position of the cell relative to the axis of the explant, with cells closer to the periphery experiencing greater FFISS than cells near the central axis of the explant. These results will allow biosynthetic activity of fibrochondrocytes to be correlated with position and morphology in the future.