Traumatic joint injury induces acute catabolic bone turnover concurrent with articular cartilage damage in a rat model of posttraumatic osteoarthritis

Maerz, Tristan; Newton, Michael D.; Fleischer, Mackenzie M; Hartner, Samantha; Gawronski, Karissa; Junginger, Lucas; Baker, Kevin C.

doi:10.1002/jor.24903

Cited by 10 publications

(6 citation statements)

References 42 publications

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“…These changes were not discernible with standard H&E or safranin-O histology techniques, which was one of the benefits of using CT for analysis. The increase of subchondral bone in the MMT model was different from the reported decrease of subchondral bone following an anterior collateral ligament tear rat injury model [24][25][26]. As others have also suggested, the different effects on the subchondral bone may be due to the difference in the post-traumatic osteoarthritis models [27].…”

Section: Discussioncontrasting

confidence: 58%

Osteoarthritis Early-, Mid- and Late-Stage Progression in the Rat Medial Meniscus Transection Model

McKinney

Pucha

et al. 2021

Preprint

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Osteoarthritis is a degenerative disease of synovial joints affecting all tissues, including the articular cartilage and underlying subchondral bone. Osteoarthritis animal models can recapitulate aspects of human disease progression and are commonly used to test the development of drugs, biomaterials, and cell therapies for treatment. The rat medial meniscus transection (MMT) model is a surgically induced post-traumatic osteoarthritis model and is one of the most commonly used models for therapeutic development; however, it is typically used to evaluate the efficacy of therapies to prevent disease development rather than testing the treatment of disease progression in already established disease. We describe herein, the qualitative and quantitative changes to articular cartilage, subchondral bone, and formation of osteophytes in rats at early- (3-weeks post-surgery), mid- (6-weeks post-surgery) and late- (12-weeks post-surgery) stages of osteoarthritis progression. Tibiae of MMT-operated animals showed loss of proteoglycan and fibrillation formation on articular cartilage surfaces as early as 3-weeks post-surgery. Using a contrast-enhanced microCT technique, quantitative, 3-dimensional analysis of the tibiae showed that the articular cartilage initially thickened at 3- and 6-weeks post-surgery and then decreased at 12-weeks post-surgery. This decrease in cartilage thickness corresponded with increased lesions in the articular cartilage, including fully degraded surfaces down to the subchondral bone layer. In this rat MMT model, subchondral bone thickening was significant at 6-weeks post-surgery and seem to follow cartilage damage. Osteophytes were found at 3-weeks post-surgery, which coincided with articular cartilage degradation. Cartilaginous osteophytes preceded mineralization suggesting that these marginal tissue growths most likely occurred through endochondral ossification. The use of the rat MMT model has predominantly been used out to 3-weeks, and most studies determine the effect of therapies to delay or prevent the onset of osteoarthritis. We provide evidence that an extension of the rat MMT model out to 6 and 12 weeks resembled more severe phenotypes of human osteoarthritis. The mid- to late-stages of rat MMT model can be used to evaluate the therapeutic efficacy of novel treatments to treat the progression of established disease --- since patients typically present in the clinic when the disease is established and becomes symptomatic, thus evaluating the efficacy of new treatments at the late stage will be important for eventual clinical translation.

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Section: Discussioncontrasting

confidence: 58%

Osteoarthritis Early-, Mid- and Late-Stage Progression in the Rat Medial Meniscus Transection Model

McKinney

Pucha

et al. 2021

Preprint

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Section: Discussionmentioning

confidence: 99%

“…Our experimental design allowed us to ask whether early bone changes following traumatic injuries affected the contralateral limb. Early subchondral bone changes to the injured limb following joint injuries in rodents are well established 6–10,17,22,23,25,27 . However, while the acute inflammatory response after injury has been shown to affect tissues far from the injury site 16 , whether bone changes to the contralateral to injured limb occur remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Subchondral bone and synovial fluid metabolomic profiles are altered in injured and contralateral limbs 7 days after non-invasive joint injury in skeletally-mature C57BL/6 mice

Hislop¹,

Devine

June

et al. 2022

Preprint

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Objective: Post-traumatic osteoarthritis (PTOA) is a common long-term outcome following ACL injury. However, early changes to bone and synovial fluid after ACL injury are not sufficiently understood. The objectives of this study were to (1) evaluate whether acute bone loss one week after ACL injury is accompanied by altered subchondral bone plate modulus, (2) determine if bone changes are localized to the injured limb or extend to the contralateral-to-injured limb compared with sham-loaded controls, and (3) identify shifts in synovial fluid metabolism unique to injured limbs. Design: Female C57Bl\6N mice (19 weeks at injury) were subjected to either a single tibial compression overload to simulate ACL injury (n=8) or a small pre-load (n=8). Mice were euthanized 7 days after injury, and synovial fluid was immediately harvested for metabolomic profiling. Bone microarchitecture, bone formation, and subchondral bone modulus at the proximal tibia were studied using microCT, histomorphometry, and nanoindentation, respectively. Osteoclast number density was assessed at the distal femur. For each bone measure a mixed model ANOVA was generated to determine the effects of injury and loaded side. Results: Epiphyseal and subchondral bone microarchitecture decreased while subchondral bone tissue modulus was unchanged after ACL injuries. Bone resorption increased but bone formation was not changed. Loss of bone microarchitecture also occurred for the contralateral-to-injured limb, demonstrating that the early response to ACL injury extended beyond the injured joint. While the metabolomic profiles of the injured and contralateral-to-injured limbs had many similarities, there were also distinct metabolic shifts present in only the injured limbs. The most prominent of the pathways was cysteine and methionine metabolism, which is associated with osteoclast activity. Conclusion: These results add to the understanding of early bone changes following ACL injury. Confirming prior reports, we observe a decline in epiphyseal and subchondral bone microarchitecture. We add the finding that subchondral bone modulus remains unchanged at one week after ACL injury. A potential biomarker of this initial bone catabolic response may be synovial fluid cysteine and methionine metabolism, which was only dysregulated in injured knees. Our results implicate a rapidly changing biological and mechanical environment within both the injured and contralateral joints that has the potential for influencing the progression to PTOA.

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“…Separate scores were determined at the femoral proximal joint margin and in epiphyseal cortical bone, and the 2 scores were summed for a composite bone erosion score of the whole joint. Metaphyseal and epiphyseal trabecular bone volumes were manually contoured in a blinded fashion and then quantitatively analyzed in 3D to derive morphometric trabecular parameters, as previously described ( 56 ) and per standardized guidelines ( 57 ). Metaphyseal and epiphyseal cortical bone volumes were derived automatically by dilation of trabecular volumes and segmenting of background and endocortical tissue.…”

Section: Methodsmentioning

confidence: 99%

Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1

Tsou¹,

Lu²,

Gurrea-Rubio³

et al. 2022

Journal of Clinical Investigation

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CD13, an ectoenzyme on myeloid and stromal cells, also circulates as a shed, soluble protein (sCD13) with powerful chemoattractant, angiogenic, and arthritogenic properties, which require engagement of a G protein–coupled receptor (GPCR). Here we identify the GPCR that mediates sCD13 arthritogenic actions as the bradykinin receptor B1 (B1R). Immunofluorescence and immunoblotting verified high expression of B1R in rheumatoid arthritis (RA) synovial tissue and fibroblast-like synoviocytes (FLSs), and demonstrated binding of sCD13 to B1R. Chemotaxis, and phosphorylation of Erk1/2, induced by sCD13, were inhibited by B1R antagonists. In ex vivo RA synovial tissue organ cultures, a B1R antagonist reduced secretion of inflammatory cytokines. Several mouse arthritis models, including serum transfer, antigen-induced, and local innate immune stimulation arthritis models, were attenuated in Cd13 –/– and B1R –/– mice and were alleviated by B1R antagonism. These results establish a CD13/B1R axis in the pathogenesis of inflammatory arthritis and identify B1R as a compelling therapeutic target in RA and potentially other inflammatory diseases.

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Traumatic joint injury induces acute catabolic bone turnover concurrent with articular cartilage damage in a rat model of posttraumatic osteoarthritis

Cited by 10 publications

References 42 publications

Osteoarthritis Early-, Mid- and Late-Stage Progression in the Rat Medial Meniscus Transection Model

Osteoarthritis Early-, Mid- and Late-Stage Progression in the Rat Medial Meniscus Transection Model

Subchondral bone and synovial fluid metabolomic profiles are altered in injured and contralateral limbs 7 days after non-invasive joint injury in skeletally-mature C57BL/6 mice

Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1

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