Early changes in morphology, bone mineral density and matrix composition of vertebrae lead to disc degeneration in aged collagen IX −/− mice

Kamper, Matthias; Hamann, Nina; Prein, Carina; Clausen‐Schaumann, Hauke; Farkas, Zsuzsanna; Aszódi, Attila; Niehoff, Anja; Paulsson, Mats; Zaucke, Frank

doi:10.1016/j.matbio.2015.09.005

Cited by 28 publications

(32 citation statements)

References 43 publications

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“…Our results, however, suggest that collagen XI plays a role in the formation and/or maintenance of cortical bone. Indeed, previous studies support our results that fibrillar collagen components play a role in bone morphogenesis and structure . Mice homozygous for the Col11a1 mutation ( cho/cho ) do not survive after birth because of improper skeletal formation, including a shortened spine and shortened bones in the appendicular and thoracic skeleton .…”

Section: Discussionsupporting

confidence: 89%

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

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Otero

Armar

et al. 2017

Journal Orthopaedic Research

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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.

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Section: Discussionsupporting

confidence: 89%

“…Col11a1 ‐deficient mice also have altered bone microarchitecture during embryonic development . In addition, mice with a deficiency in collagen IX, another key component of collagen fibrils in the cartilage ECM, have abnormal skeletal properties . Lastly, Col11a2 mutations lead to mild dwarfism in Labrador retrievers .…”

Section: Discussionmentioning

confidence: 99%

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

Holyoak

Otero

Armar

et al. 2017

Journal Orthopaedic Research

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“…Interestingly, the absence of Tnmd in tendon versus OAF tissues caused the opposite effect on the mRNA expression levels of several ECM genes such as Col14a1 , Col15a1, and Prg4, as well as the transcription factors Scx , a direct transactivator of Tnmd (Shukunami et al, ), and Mkx , both known to regulate collagens. Furthermore, we detected elevated expression of MMP‐3 and MMP‐9 in Tnmd −/− OAF cells; thus, soluble matrix proteins can be extruded from the tissue by mechanical loading and enhance the degenerative process (Kamper et al, ). Notably, the glycosaminoglycan to hydroxyproline ratio within the NP of young adults is approximately 27:1, whereas the ratio within the hyaline cartilage of the same individuals is about 2:1 (Mwale et al, ).…”

Section: Discussionmentioning

confidence: 99%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin (Tnmd) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of Tnmd. Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. Tnmd knockout (Tnmd−/−) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, Tnmd and chondromodulin I (Chm1, the only homologous gene to Tnmd) double knockout (Tnmd−/−Chm1−/−) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of Tnmd in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration.

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“…Measurements were taken with NanoWizard AFM instrument (JPK Instruments, Berlin, Germany) mounted on an inverted optical microscope (Axiovert 200, Zeiss) according to (Kamper et al, 2016, Prein et al, 2016) with slight modifications. To identify and ensure comparable regions between the groups, every 10th slide was analyzed by H&E staining and consecutive slides were taken for AFM.…”

Section: Methodsmentioning

confidence: 99%

Tenomodulin is Required for Tendon Endurance Running and Collagen I Fibril Adaptation to Mechanical Load

et al. 2017

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Tendons are dense connective tissues that attach muscles to bone with an indispensable role in locomotion because of their intrinsic properties of storing and releasing muscle- generated elastic energy. Tenomodulin (Tnmd) is a well-accepted gene marker for the mature tendon/ligament lineage and its loss-of -function in mice leads to a phenotype with distinct signs of premature aging on tissue and stem/progenitor cell levels. Based on these findings, we hypothesized that Tnmd might be an important factor in the functional performance of tendons. Firstly, we revealed that Tnmd is a mechanosensitive gene and that the C-terminus of the protein co-localize with collagen I-type fibers in the extracellular matrix. Secondly, using an endurance training protocol, we compared Tnmd knockout mice with wild types and showed that Tnmd deficiency leads to significantly inferior running performance that further worsens with training. In these mice, endurance running was hindered due to abnormal response of collagen I cross-linking and proteoglycan genes leading to an inadequate collagen I fiber thickness and elasticity. In sum, our study demonstrates that Tnmd is required for proper tendon tissue adaptation to endurance running and aids in better understanding of the structural-functional relationships of tendon tissues.

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Early changes in morphology, bone mineral density and matrix composition of vertebrae lead to disc degeneration in aged collagen IX −/− mice

Cited by 28 publications

References 43 publications

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

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

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Tenomodulin is Required for Tendon Endurance Running and Collagen I Fibril Adaptation to Mechanical Load

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