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The periosteal requirement and temporal dynamics of BMP2-induced middle phalanx regeneration in the adult mouse.

ABSTRACT: Regeneration of mammalian limbs is restricted to amputation of the distal digit tip, the terminal phalanx (P3). The adjacent skeletal element, the middle phalanx (P2), has emerged as a model system to investigate regenerative failure and as a site to test approaches aimed at enhancing regeneration. We report that exogenous application of bone morphogenetic protein 2 (BMP2) stimulates the formation of a transient cartilaginous callus distal to the amputation plane that mediates the regeneration of the amputated P2 bone. BMP2 initiates a significant regeneration response during the periosteal-derived cartilaginous healing phase of P2 bone repair, yet fails to induce regeneration in the absence of periosteal tissue, or after boney callus formation. We provide evidence that a temporal component exists in the induced regeneration of P2 that we define as the "regeneration window." In this window, cells are transiently responsive to BMP2 after the amputation injury. Simple re-injury of the healed P2 stump acts to reinitiate endogenous bone repair, complete with periosteal chondrogenesis, thus reopening the "regeneration window" and thereby recreating a regeneration-permissive environment that is responsive to exogenous BMP2 treatment.

SUBMITTER: Dawson LA

PROVIDER: S-EPMC5617898 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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The periosteal requirement and temporal dynamics of BMP2-induced middle phalanx regeneration in the adult mouse.

Dawson Lindsay A LA Yu Ling L Yan Mingquan M Marrero Luis L Schanes Paula P PP Dolan Connor C Pela Maegan M Petersen Britta B Han Manjong M Muneoka Ken K

Regeneration (Oxford, England) 20170601 3

Regeneration of mammalian limbs is restricted to amputation of the distal digit tip, the terminal phalanx (P3). The adjacent skeletal element, the middle phalanx (P2), has emerged as a model system to investigate regenerative failure and as a site to test approaches aimed at enhancing regeneration. We report that exogenous application of bone morphogenetic protein 2 (BMP2) stimulates the formation of a transient cartilaginous callus distal to the amputation plane that mediates the regeneration o ...[more]

PMID: 28975034

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Project description:BackgroundIn limb regeneration of amphibians, the early steps leading to blastema formation are critical for the success of regeneration, and the initiation of regeneration in an adult limb requires the presence of nerves. Xenopus laevis tadpoles can completely regenerate an amputated limb at the early limb bud stage, and the metamorphosed young adult also regenerates a limb by a nerve-dependent process that results in a spike-like structure. Blockage of Wnt/?-catenin signaling inhibits the initiation of tadpole limb regeneration, but it remains unclear whether limb regeneration in young adults also requires Wnt/?-catenin signaling.Methodology/principal findingsWe expressed heat-shock-inducible (hs) Dkk1, a Wnt antagonist, in transgenic Xenopus to block Wnt/?-catenin signaling during forelimb regeneration in young adults. hsDkk1 did not inhibit limb regeneration in any of the young adult frogs, though it suppressed Wnt-dependent expression of genes (fgf-8 and cyclin D1). When nerve supply to the limbs was partially removed, however, hsDkk1 expression blocked limb regeneration in young adult frogs. Conversely, activation of Wnt/?-catenin signaling by a GSK-3 inhibitor rescued failure of limb-spike regeneration in young adult frogs after total removal of nerve supply.Conclusions/significanceIn contrast to its essential role in tadpole limb regeneration, our results suggest that Wnt/?-catenin signaling is not absolutely essential for limb regeneration in young adults. The different requirement for Wnt/?-catenin signaling in tadpoles and young adults appears to be due to the projection of nerve axons into the limb field. Our observations suggest that nerve-derived signals and Wnt/?-catenin signaling have redundant roles in the initiation of limb regeneration. Our results demonstrate for the first time the different mechanisms of limb regeneration initiation in limb buds (tadpoles) and developed limbs (young adults) with reference to nerve-derived signals and Wnt/?-catenin signaling.

Dataset Information

The periosteal requirement and temporal dynamics of BMP2-induced middle phalanx regeneration in the adult mouse.

Publications

The periosteal requirement and temporal dynamics of BMP2-induced middle phalanx regeneration in the adult mouse.

Similar Datasets

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