Scleraxis is required for the development of a functional tendon enthesis

Killian, Megan L.; Thomopoulos, Stavros

doi:10.1096/fj.14-258236

Cited by 75 publications

(74 citation statements)

References 47 publications

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“…As discussed earlier, deletion of Scx results in loss of bone eminences, but the basic ability of tendon to attach to skeleton is not impaired. At postnatal stages however, organization and mineralization of the enthesis is subsequently disrupted in Scx mutants (Killian and Thomopoulos, 2016). It is still not completely clear whether these defects are due directly to Scx function in enthesis cells, since tendons are also drastically impaired in Scx mutants and postnatal pups show limited mobility, which could therefore affect mechanical loading of the enthesis.…”

Section: Enthesesmentioning

confidence: 99%

Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton

Huang

2017

Developmental Biology

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Functional movement and stability of the limb depends on an organized and fully integrated musculoskeletal system composed of skeleton, muscle, and tendon. Much of our current understanding of musculoskeletal development is based on studies that focused on the development and differentiation of individual tissues. Likewise, research on patterning events have been largely limited to the primary skeletal elements and the mechanisms that regulate soft tissue patterning, the development of the connections between tissues, and their interdependent development are only beginning to be elucidated. This review will therefore highlight recent exciting discoveries in this field, with an emphasis on tendon and muscle patterning and their integrated development with the skeleton and skeletal attachments.

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Section: Enthesesmentioning

confidence: 99%

Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton

Huang

2017

Developmental Biology

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“…Because it has been reported that the forces applied by muscles and tendons to the enthesis are important for bone ridge formation, we investigated the effects of mechanical unloading using tendon‐severing operation or hindlimb unloading in tail‐suspended mice. We found that bone eminences in Anxa5 –/– mice were reduced to levels comparable to those in Anxa5 +/+ mice by 8 weeks after tenotomy or hindlimb unloading, suggesting that bone eminence formation in response to mechanical tension is restricted by expression of Anxa5.…”

Section: Discussionmentioning

confidence: 99%

Annexin A5 Involvement in Bone Overgrowth at the Enthesis

Shimada

Ideno

Arai

et al. 2018

Journal of Bone and Mineral Research

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Little is known about the molecular mechanisms of enthesis formation in mature animals. Here, we report that annexin A5 (Anxa5) plays a critical role in the regulation of bone ridge outgrowth at the entheses. We found that Anxa5 is highly expressed in the entheses of postnatal and adult mice. In Anxa5-deficient (Anxa5 ) mice, the sizes of bone ridge outgrowths at the entheses of the tibias and femur were increased after age 7 weeks. Bone overgrowth was not observed at the fibrous enthesis where the fibrocartilage layer does not exist. More ALP-expressing cells were observed in the fibrocartilage layer in Anxa5 mice than in wild-type (WT) mice. Calcein and Alizarin Red double labeling revealed more mineralized areas in Anxa5 mice than WT mice. To examine the effects of mechanical forces, we performed tenotomy in which transmission of contractile forces by the tibial muscle was impaired by surgical muscle release. In tenotomized mice, bone overgrowth at the enthesis in Anxa5 mice was decreased to a level comparable to that in WT mice at 8 weeks after the operation. The tail-suspended mice also showed a decrease in bone overgrowth to similar levels in Anxa5 and WT mice at 8 weeks after hindlimb unloading. These results suggest that bone overgrowth at the enthesis requires mechanical forces. We further examined effects of Anxa5 gene knockdown (KD) in primary cultures of osteoblasts, chondrocytes, and tenocytes in vitro. Anxa5 KD increased ALP expression in tenocytes and chondrocytes but not in osteoblasts, suggesting that increased ALP activity in the fibrocartilaginous tissue in Anxa5 mice is directly caused by Anxa5 deletion in tenocytes or fibrocartilage cells. These data indicate that Anxa5 prevents bone overgrowth at the enthesis, whose formation is mediated through mechanical forces and modulating expression of mineralization regulators. © 2018 American Society for Bone and Mineral Research.

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“…Prx1Cre mice (strain 005584) were purchased from The Jackson Laboratory. The genotypes of mice were determined from toe and tail biopsies by using PCR-based analysis of DNA for Cre, Scx-null, Scx-WT, and Scx-flox alleles (13,22). Scx-mutant mice were developed by using Scx flx/flx mice crossed with Prx1-Cre; Scx flx/WT mice.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Although dispensable in small animal models of long bone fracture healing (12), the role of BMP-4 in long bone development is evident. Recent work has shed light on the development of bone ridges in long bones, specifically at the interface between tendon and bone (13)(14)(15)(16)(17)(18)(19)(20). The shape and formation of bone ridges on skeletal elements is regulated, first, by specification of progenitors by TGF-b, followed by differentiation mediated by BMP-4 and scleraxis (Scx), a tendon progenitor marker (15,19).…”

mentioning

confidence: 99%

“…Scx is a member of the basic helix-loop-helix family of transcription factors and is critical for the proper ABBREVIATIONS: BMP, bone morphogenetic protein; BTX, botulinum toxin A; BW, body weight; CID, creep indentation distance; Ct.Ar., cortical area; GFP, green fluorescent protein; I, polar moment of inertia; ID 1st, first cycle indentation distance; IDI, indentation distance increase; microCT, microcomputed tomography; MOI, moment of inertia; PYD, postyield displacement; qRT-PCR, quantitative RT-PCR; Scx, scleraxis; ScxGFP, scleraxis green fluorescent protein-labeled; Scx-mutant, scleraxis knockout; TID, total indentation distance; TMD, tissue mineral density; US 1st, first cycle unloading slope; WT, wild-type development and maturation of tendons (18,22,(25)(26)(27) and their attachments to bone (13)(14)(15). Loss of Scx leads to impaired, but not complete absence of, tendon formation (22).…”

mentioning

confidence: 99%

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Loss of scleraxis in mice leads to geometric and structural changes in cortical bone, as well as asymmetry in fracture healing

et al. 2016

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Scleraxis (Scx) is a known regulator of tendon development, and recent work has identified the role of Scx in bone modeling. However, the role of Scx in fracture healing has not yet been explored. This study was conducted to identify the role of Scx in cortical bone development and fracture healing. Scx green fluorescent protein-labeled (ScxGFP) reporter and Scx-knockout (Scx-mutant) mice were used to assess bone morphometry and the effects of fracture healing on Scx localization and gene expression, as well as callus healing response. Botulinum toxin (BTX) was used to investigate muscle unloading effects on callus shape. Scx-mutant long bones had structural and mechanical defects. gene expression was elevated and was decreased at 24 h after fracture. ScxGFP cells were localized throughout the healing callus after fracture. Scx-mutant mice demonstrated disrupted callus healing and asymmetry. Asymmetry of Scx-mutant callus was not due to muscle unloading. Wild-type littermates (age matched) served as controls. This is the first study to explore the role of Scx in cortical bone mechanics and fracture healing. Deletion of Scx during development led to altered long bone properties and callus healing. This study also demonstrated that Scx may play a role in the periosteal response during fracture healing.-McKenzie, J. A., Buettmann, E., Abraham, A. C., Gardner, M. J., Silva, M. J., Killian, M. L. Loss of scleraxis in mice leads to geometric and structural changes in cortical bone, as well as asymmetry in fracture healing.

show abstract

Scleraxis is required for the development of a functional tendon enthesis

Cited by 75 publications

References 47 publications

Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton

Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton

Annexin A5 Involvement in Bone Overgrowth at the Enthesis

Loss of scleraxis in mice leads to geometric and structural changes in cortical bone, as well as asymmetry in fracture healing

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