Collagen XI mutation lowers susceptibility to load‐induced cartilage damage in mice

Abstract

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.

The mechanical impact ofcol11a2loss on joints;col11a2mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis

“…Type II collagen degradation [ 16 ] and early-onset OA were reported in Cho/+ heterozygous mice [ 17 ]. Additionally, mice haploinsufficient for Col11a1 display altered susceptibility to load-induced damage [ 18 ]. While Col11a2 mutant mice have been reported to show hearing loss, their skeletal phenotype has not been described [ 19 ].…”

T cells Mediate Progression of Load-Induced Osteoarthritis

“…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.…”

“…Knee joints were harvested and fixed in 4% paraformaldehyde and scanned in 70% ethanol at 15μm voxel resolution (μCT35, Scanco, Bruttisellen, Switzerland; 55 kVp, 145mA, 600 ms integration time), as reported earlier (9,17). Cancellous and cortical bone in the epiphysis and metaphysis of the proximal tibia were analyzed to assess bone morphology using microcomputed tomography (microCT).…”

“…Osteophyte maturity (35) was evaluated based on the degree of calcification of ectopic bone. Osteophyte size was based on the medial-lateral width, defined as the distance between the medial end of the epiphysis and the end of the osteophyte; the mean width was calculated for each limb (9).…”

Musculoskeletal mechanobiology: A new era for MechanoMedicine

“…This special issue begins with several outstanding reviews that provide updates on the significance of mechanobiology in musculoskeletal research involving cartilage, tendon, muscle and bone, [1][2][3][4][5][6][7][8][9][10] and that span topics from the role of candidate mechanosensors and chemical mediators, 1,5,9,10 in vitro and in vivo models of tissue injury and repair, 3,4 and supporting technologies. 6,7 The majority of original articles following the review papers are related to the mechanobiology of bone and cartilage, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] tissues whose physical regulation have traditionally garnered intensive research focus, followed by complementary research papers in areas of growing prominence: Ligaments, intervertebral discs, and stem cells. [24][25][26][27][28] From this Special Issue in Musculoskeletal Mechanobiology, it is clear that it has become technically possible to trace the impact of mechanics from individual molecules to an entire organism.…”