Joint degeneration following closed intraarticular fracture in the mouse knee: A model of posttraumatic arthritis

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127

Objective. Posttraumatic arthritis is a frequent long-term complication of intraarticular fractures. A model of a closed intraarticular fracture in C57BL/6 mice that progresses to posttraumatic arthritis has been developed. The MRL/MpJ mouse has shown unique regenerative abilities in response to injury. The objective of this study was to determine if the MRL/MpJ mouse is protected from posttraumatic arthritis after intraarticular fractures.Methods. Intraarticular fractures were created in MRL/MpJ mice and C57BL/6 control mice (n ‫؍‬ 16 each). Limbs were analyzed for posttraumatic arthritis 4 and 8 weeks after fracture using microfocal computed tomography bone morphology, subchondral bone thickness evaluation, and histologic evaluation of cartilage degeneration. Serum cytokines and biomarkers were measured after the mice were killed.Results. Intraarticular fractures were successfully created in all 32 mice. In the experimental fractured limbs, C57BL/6 mice had a decrease in bone density, increased subchondral bone thickness, and increased cartilage degeneration compared with normal contralateral control limbs. In the MRL/MpJ mice, no differences in bone density, subchondral bone thickness, or histologic grading of cartilage degeneration were seen between fractured and contralateral control limbs. Cytokine analysis showed lower systemic levels of the proinflammatory cytokine interleukin-1␣ (IL-1␣) and higher levels of the antiinflammatory cytokines IL-4 and IL-10 in the MRL/MpJ mice.Conclusion. This study shows that the MRL/MpJ mouse is relatively protected from posttraumatic arthritis after intraarticular fracture. Further investigation into the mechanism involved in this response will hopefully provide new insight into the pathogenesis, prevention, and treatment of posttraumatic arthritis after intraarticular fracture.

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse

Ward¹,

Furman²,

Huebner³

et al. 2008

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112

127

Decreased physical function and increased pain sensitivity in mice deficient for type IX collagen

Allen¹,

Griffin²,

Rodriguiz³

et al. 2009

Objective. In mice with Col9a1 gene inactivation (Col9a1 ؊/؊ ), osteoarthritis (OA) and intervertebral disc degeneration develop prematurely. The aim of this study was to investigate Col9a1 ؊/؊ mice for functional and symptomatic changes that may be associated with these pathologies.Methods. Col9a1 ؊/؊ and wild-type mice were investigated for reflexes, functional impairment (beam walking, pole climbing, wire hang, grip strength), sensorimotor skills (rotarod), mechanical sensitivity (von Frey hair), and thermal sensitivity (hot plate/tail flick). Gait was also analyzed to determine velocity, stride frequency, symmetry, percentage stance time, stride length, and step width. Postmortem, sera obtained from the mice were analyzed for hyaluronan, and their knees and spines were graded histologically for degeneration.Results. Col9a1 ؊/؊ mice had compensatory gait changes, increased mechanical sensitivity, and impaired physical ability. Col9a1 ؊/؊ mice ambulated with gaits characterized by increased percentage stance times and shorter stride lengths. These mice also had heightened mechanical sensitivity and were deficient in contact righting, wire hang, rotarod, and pole climbing tasks. Male Col9a1 ؊/؊ mice had the highest mean serum hyaluronan levels and strong histologic evidence of cartilage erosion. Intervertebral disc degeneration was also detected, with Col9a1 ؊/؊ mice having an increased incidence of disc tears.Conclusion. These data describe a Col9a1 ؊/؊ behavioral phenotype characterized by altered gait, increased mechanical sensitivity, and impaired function. These gait and functional differences suggest that Col9a1 ؊/؊ mice select locomotive behaviors that limit joint loads. The nature and magnitude of behavioral changes were largest in male mice, which also had the greatest evidence of knee degeneration. These findings suggest that Col9a1 ؊/؊ mice present behavioral changes consistent with anatomic signs of OA and intervertebral disc degeneration.Osteoarthritis (OA) and degenerative disc disease (DDD) are common musculoskeletal disorders, and, as chronic conditions, both have large economic costs (1). Clinically, OA and DDD are associated with joint pain, loss of function, and decreased quality of life. A genetic predisposition to musculoskeletal diseases has been suggested as a determinant of individual risk (2,3), and extracellular matrix mutations have been linked to the premature onset of OA and DDD (4-10). Type IX collagen is a heterotrimeric collagen that associates with type II collagen fibrils and contains domains suited to promote extracellular matrix cohesion (11). Type IX collagen mutations are hypothesized to weaken cartilaginous tissues (8). Mice with inactivation of the Col9a1 gene, henceforth referred to as Col9a1 Ϫ/Ϫ mice, do not form functional type IX collagen molecules (12) and experience spontaneous development of premature cartilage degeneration (as early as 3 months) in the intervertebral disc, knee, and temporomandibular joint that worsens with age (up to 12 months) (12-14). It is not...

Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4

Coles¹,

Zhang²,

Blum³

et al. 2010

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122

ObjectiveTo assess the role of the glycoprotein PRG4 in joint lubrication and chondroprotection by measuring friction, stiffness, surface topography, and subsurface histology of the hip joints of Prg4−/− and wild-type (WT) mice.MethodsFriction and elastic modulus were measured in cartilage from the femoral heads of Prg4−/− and WT mice ages 2, 4, 10, and 16 weeks using atomic force microscopy, and the surface microstructure was imaged. Histologic sections of each femoral head were stained and graded.ResultsHistologic analysis of the joints of Prg4−/− mice showed an enlarged, fragmented surface layer of variable thickness with Safranin O–positive formations sometimes present, a roughened underlying articular cartilage surface, and a progressive loss of pericellular proteoglycans. Friction was significantly higher on cartilage of Prg4−/− mice at age 16 weeks, but statistically significant differences in friction were not detected at younger ages. The elastic modulus of the cartilage was similar between cartilage surfaces of Prg4−/− and WT mice at young ages, but cartilage of WT mice showed increasing stiffness with age, with significantly higher moduli than cartilage of Prg4−/− mice at older ages.ConclusionDeletion of the gene Prg4 results in significant structural and biomechanical changes in the articular cartilage with age, some of which are consistent with osteoarthritic degeneration. These findings suggest that PRG4 plays a significant role in preserving normal joint structure and function.