Primary cilia act as mechanosensors during bone healing around an implant

Leucht, Philipp; Monica, Stefanie D.; Temiyasathit, Sara; Lenton, Kelly A.; Manu, Alina; Longaker, Michael T.; Jacobs, Christopher R.; Spilker, Robert L.; Guo, Haijie; Brunski, John B.; Helms, Jill A.

doi:10.1016/j.medengphy.2012.06.005

Cited by 32 publications

(25 citation statements)

References 54 publications

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“…The surgical procedure, the osseointegration response, and the molecular and cellular characteristics of this process have been documented elsewhere [6,11,14,15,17,26,27]. Here, we show that new bone, originating from the tibial marrow cavity, is first evident on post-surgical day 5 (Supplemental Fig.…”

Section: Resultssupporting

confidence: 70%

“…Using this information we have identified principal strains in the 10–20% range to stimulate osseointegration [13,14]. Genetic mouse models have been particularly helpful in identifying key variables that influence osseointegration; namely, we demonstrated that early excessive micromotion can cause fibrous encapsulation [15] and the elimination of mechanically sensitive cellular appendages such as primary cilia can obliterate the strain-induced bone formation [16,17]. …”

Section: Introductionmentioning

confidence: 99%

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A pre-clinical murine model of oral implant osseointegration

Mouraret¹,

Hunter²,

Bardet³

et al. 2014

Bone

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Many of our assumptions concerning oral implant osseointegration are extrapolated from experimental models studying skeletal tissue repair in long bones. This disconnect between clinical practice and experimental research hampers our understanding of bone formation around oral implants and how this process can be improved. We postulated that oral implant osseointegration would be fundamentally equivalent to implant osseointegration elsewhere in the body. Mice underwent implant placement in the edentulous ridge anterior to the first molar and peri-implant tissues were evaluated at various timepoints after surgery. Our hypothesis was disproven; oral implant osseointegration is substantially different from osseointegration in long bones. For example, in the maxilla peri-implant pre-osteoblasts are derived from cranial neural crest whereas in the tibia peri-implant osteoblasts are derived from mesoderm. In the maxilla, new osteoid arises from periostea of the maxillary bone but in the tibia the new osteoid arises from the marrow space. Cellular and molecular analyses indicate that osteoblast activity and mineralization proceeds from the surfaces of the native bone and osteoclastic activity is responsible for extensive remodeling of the new peri-implant bone. In addition to histologic features of implant osseointegration, molecular and cellular assays conducted in a murine model provide new insights into the sequelae of implant placement and the process by which bone is generated around implants.

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Section: Resultssupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

A pre-clinical murine model of oral implant osseointegration

Mouraret¹,

Hunter²,

Bardet³

et al. 2014

Bone

Self Cite

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“…Leucht et al utilized Col1α1-Cre and Kif3a fl/fl mice to generate conditional knockout of Kif3a in osteoblasts and investigate the role of primary cilia in bone repair [22,23]. No skeletal abnormalities or aberrations in skeletal patterning were detected in embryos, pups or adult mice.…”

Section: Proposed Mechanosensory Roles Of Primary Cilia In Osteocytesmentioning

confidence: 99%

Emerging role of primary cilia as mechanosensors in osteocytes

Nguyẽ̂n

Jacobs

2013

Bone

101

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The primary cilium is a solitary, immotile microtubule-based extension present on nearly every mammalian cell. This organelle has established mechanosensory roles in several contexts including kidney, liver, and the embryonic node. Mechanical load deflects the cilium, triggering biochemical responses. Defects in cilium function have been associated with numerous human diseases. Recent research has implicated the primary cilium as a mechanosensor in bone. In this review, we discuss the cilium, the growing evidence for its mechanosensory role in bone, and areas of future study. This article is part of a Special Issue entitled “Osteocytes”.

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“…Deletion of Kif3a in osteoblasts/osteocytes impairs responses to load-induced bone formation, fluid flow shear stress, and strain fields caused by implant displacement, suggesting that primary cilia play an essential role in bone remodeling. (25)(26)(27) However, the role of IFT proteins in regulating fracture healing has not been investigated. The purpose of this study is to investigate the role of IFT80 in fracture healing, focusing on how it affects chondrocytes.…”

Section: Introductionmentioning

confidence: 99%

IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF-β Signaling in Chondrocyte Differentiation and Function

Liu

Alharbi

Graves

et al. 2019

Journal of Bone and Mineral Research

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Primary cilia are essential cellular organelles that are anchored at the cell surface membrane to sense and transduce signaling. Intraflagellar transport (IFT) proteins are indispensable for cilia formation and function. Although major advances in understanding the roles of these proteins in bone development have been made, the mechanisms by which IFT proteins regulate bone repair have not been identified. We investigated the role of the IFT80 protein in chondrocytes during fracture healing by creating femoral fractures in mice with conditional deletion of IFT80 in chondrocytes utilizing tamoxifen inducible Col2α1‐CreER mice. Col2α1creIFT80f/f mice had smaller fracture calluses than IFT80f/f (control) mice. The max‐width and max‐callus area were 31% and 48% smaller than those of the control mice, respectively. Col2α1creIFT80f/f mice formed low‐density/porous woven bony tissue with significantly lower ratio of bone volume, Trabecular (Tb) number and Tb thickness, and greater Tb spacing compared to control mice. IFT80 deletion significantly downregulated the expression of angiogenesis markers‐VEGF, PDGF and angiopoietin and inhibited fracture callus vascularization. Mechanistically, loss of IFT80 in chondrocytes resulted in a decrease in cilia formation and chondrocyte proliferation rate in fracture callus compared to the control mice. Meanwhile, IFT80 deletion downregulated the TGF‐β signaling pathway by inhibiting the expression of TGF‐βI, TGF‐βR, and phosphorylation of Smad2/3 in the fracture callus. In primary chondrocyte cultures in vitro, IFT80 deletion dramatically reduced chondrocyte proliferation, cilia assembly, and chondrogenic gene expression and differentiation. Collectively, our findings demonstrate that IFT80 and primary cilia play an essential role in fracture healing, likely through controlling chondrocyte proliferation and differentiation, and the TGF‐β signaling pathway. © 2019 American Society for Bone and Mineral Research.

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Primary cilia act as mechanosensors during bone healing around an implant

Cited by 32 publications

References 54 publications

A pre-clinical murine model of oral implant osseointegration

A pre-clinical murine model of oral implant osseointegration

Emerging role of primary cilia as mechanosensors in osteocytes

IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF-β Signaling in Chondrocyte Differentiation and Function

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