Stimulation of osteogenic activity in mesenchymal stem cells by FK506

Dai, Wei; Dong, Jian; Fang, Taolin; Uemura, Toshimasa

doi:10.1002/jbm.a.31685

Cited by 16 publications

(14 citation statements)

References 24 publications

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“…FK506 may also directly influence osteoblast and osteoclast activity [54–58] and thereby improve fracture healing. Notably, FK506 has also been shown to promote osteogenic differentiation of mesenchymal stem cells via BMP receptor signaling in vitro [15] , highlighting the potential utility of this compound as an osteoinductive agent.…”

Section: Discussionmentioning

confidence: 99%

Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

Hurtgen

Henderson

Ward

et al. 2017

BMC Musculoskelet Disord

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Background: Heightened local inflammation due to muscle trauma or disease is associated with impaired bone regeneration. Methods: We hypothesized that FK506, an FDA approved immunomodulatory compound with neurotrophic and osteogenic effects, will rescue the early phase of fracture healing which is impaired by concomitant muscle trauma in male (~4 months old) Lewis rats. FK506 (1 mg/kg; i.p.) or saline was administered systemically for 14 days after an endogenously healing tibia osteotomy was created and fixed with an intermedullary pin, and the overlying tibialis anterior (TA) muscle was either left uninjured or incurred volumetric muscle loss injury (6 mm full thickness biopsy from middle third of the muscle). Results: The salient observations of this study were that 1) concomitant TA muscle trauma impaired recovery of tibia mechanical properties 28 days post-injury, 2) FK506 administration rescued the recovery of tibia mechanical properties in the presence of concomitant TA muscle trauma but did not augment mechanical recovery of an isolated osteotomy (no muscle trauma), 3) T lymphocytes and macrophage presence within the traumatized musculature were heightened by trauma and attenuated by FK506 3 days post-injury, and 4) T lymphocyte but not macrophage presence within the fracture callus were attenuated by FK506 at 14 days post-injury. FK506 did not improve TA muscle isometric torque production

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Section: Discussionmentioning

confidence: 99%

Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

Hurtgen

Henderson

Ward

et al. 2017

BMC Musculoskelet Disord

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“…9 Several small molecules, such as statins and immunosuppressants (e.g., FK506, cyclosporine A), have been shown to induce osteogenic differentiation in vitro and bone formation in vivo. [10][11][12][13] In particular, phenamil is a derivative of the FDA-approved diuretic amiloride, and it has been found to be a strong activator of BMP signaling.…”

Section: Introductionmentioning

confidence: 99%

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

Fan

Cui

et al. 2015

Tissue Engineering Part A

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Bone morphogenetic proteins (BMPs) have been widely used for bone repair in the craniofacial region. However, its high dose requirement in clinical applications revealed adverse effects and inefficient bone formation, along with high cost. Here, we report a novel osteoinductive strategy to effectively complement the osteogenic activity of BMP-2 using phenamil, a small molecule that can induce osteogenic differentiation via stimulation of BMP signaling. Treatment of adipose-derived stem cells (ASCs) with BMP-2 in combination with phenamil significantly promoted the in vitro osteogenic differentiation of ASCs. The efficacy of the combination strategy of phenamil + BMP-2 was further confirmed in a mouse calvarial defect model using scaffolds consisting of poly(lactic-co-glycolic acid) and apatite layer on their surfaces designed to slowly release phenamil and BMP-2. Six weeks after implantation, the scaffolds treated with phenamil + BMP-2 significantly promoted mouse calvarial regeneration as demonstrated by micro-computerized tomography and histology, compared with the groups treated with phenamil or BMP-2 alone. Moreover, the combination treatment reduced the BMP-2 dose without compromising calvarial healing efficacy. These results suggest promising complementary therapeutic strategies for bone repair in more efficient and cost-effective manners.

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“…A popular model, in particular when using allogeneic or xenogeneic cells, is the nude mouse model in which TE constructs are implanted subcutaneously in the back of athymic mice [12][13][14][15][16][17]. The advantages of this model are (i) that no immunosuppressant agents, that may affect the osteogenic process need to be administered [18,19] and (ii ) that most biomaterials rarely induce bone in rodents, allowing better evaluation of an engineered implant [20].When assessing cell seeded implants, the amount of bone formed is not only dependent on the specific physicochemical…”

mentioning

confidence: 99%

A clinically relevant model of osteoinduction: a process requiring calcium phosphate and BMP/Wnt signalling

Eyckmans

Roberts

Schrooten

et al. 2010

J Cellular Molecular Medi

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In this study, we investigated a clinically relevant model of in vivo ectopic bone formation utilizing human periosteum derived cells (HPDCs) seeded in a Collagraft™ carrier and explored the mechanisms by which this process is driven. Bone formation occurred after eight weeks when a minimum of one million HPDCs was loaded on Collagraft™ carriers and implanted subcutaneously in NMRI nu/nu mice. De novo bone matrix, mainly secreted by the HPDCs, was found juxta-proximal of the calcium phosphate (CaP) granules suggesting that CaP may have triggered the ‘osteoinductive program’. Indeed, removal of the CaP granules by ethylenediaminetetraacetic acid decalcification prior to cell seeding and implantation resulted in loss of bone formation. In addition, inhibition of endogenous bone morphogenetic protein and Wnt signalling by overexpression of the secreted antagonists Noggin and Frzb, respectively, also abrogated osteoinduction. Proliferation of the engrafted HPDCs was strongly reduced in the decalcified scaffolds or when seeded with adenovirus-Noggin/Frzb transduced HPDCs indicating that cell division of the engrafted HPDCs is required for the direct bone formation cascade. These data suggest that this model of bone formation is similar to that observed during physiological intramembranous bone development and may be of importance when investigating tissue engineering strategies.

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Stimulation of osteogenic activity in mesenchymal stem cells by FK506

Cited by 16 publications

References 24 publications

Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

A clinically relevant model of osteoinduction: a process requiring calcium phosphate and BMP/Wnt signalling

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