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      BMP-7 accelerates the differentiation of rabbit mesenchymal stem cells into cartilage through the Wnt/β-catenin pathway

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          Abstract

          Mesenchymal stem cells (MSCs) are able to differentiate into adipocytes, chondroblasts or cartilage under different stimulation conditions. Identifying a mechanism that triggers the differentiation of MSCs into cartilage may help the development of novel therapeutic approaches for heterotopic ossification, the pathological formation of lamellar bone in soft tissue outside the skeleton that may lead to debilitating immobility. Bone morphogenetic proteins (BMPs), including BMP-7, are the most potent growth factors for enhancing bone formation. The current study aimed to understand the potential involvement of the Wnt/β-catenin signaling pathway in the BMP-7-induced growth of rabbit MSCs (rMSCs). Different concentrations of BMP-7 were applied to cultured rMSCs, and proliferation was evaluated by MTT assay. Changes in the phosphorylation state of glycogen synthase kinase (GSK)-3β, in addition to the expression levels of alkaline phosphatase, β-catenin and runt-related transcription factor 2 were observed by western blot analysis. Following treatment with BMP-7, the phosphorylation of GSK-3β was stimulated and the expression of β-catenin, ALP and Runx2 was increased. Furthermore, inhibiting β-catenin signaling with XAV-939 suppressed the BMP-7-mediated changes. The results indicated that the BMP-7-induced differentiation of rMSCs into cartilage was promoted primarily by the Wnt/β-catenin pathway.

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          Osteocyte Wnt/beta-catenin signaling is required for normal bone homeostasis.

          Ina Kramer, Christine Halleux, Hansjoerg Keller … (2010)
          Beta-Catenin-dependent canonical Wnt signaling plays an important role in bone metabolism by controlling differentiation of bone-forming osteoblasts and bone-resorbing osteoclasts. To investigate its function in osteocytes, the cell type constituting the majority of bone cells, we generated osteocyte-specific beta-catenin-deficient mice (Ctnnb1(loxP/loxP); Dmp1-Cre). Homozygous mutants were born at normal Mendelian frequency with no obvious morphological abnormalities or detectable differences in size or body weight, but bone mass accrual was strongly impaired due to early-onset, progressive bone loss in the appendicular and axial skeleton with mild growth retardation and premature lethality. Cancellous bone mass was almost completely absent, and cortical bone thickness was dramatically reduced. The low-bone-mass phenotype was associated with increased osteoclast number and activity, whereas osteoblast function and osteocyte density were normal. Cortical bone Wnt/beta-catenin target gene expression was reduced, and of the known regulators of osteoclast differentiation, osteoprotegerin (OPG) expression was significantly downregulated in osteocyte bone fractions of mutant mice. Moreover, the OPG levels expressed by osteocytes were higher than or comparable to the levels expressed by osteoblasts during skeletal growth and at maturity, suggesting that the reduction in osteocytic OPG and the concomitant increase in osteocytic RANKL/OPG ratio contribute to the increased number of osteoclasts and resorption in osteocyte-specific beta-catenin mutants. Together, these results reveal a crucial novel function for osteocyte beta-catenin signaling in controlling bone homeostasis.
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            Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells.

            Cláudia Gaspar, Clemens A Blitterswijk, Ramakrishnaiah Siddappa … (2004)
            Human mesenchymal stem cells (hMSCs) from the bone marrow represent a potential source of pluripotent cells for autologous bone tissue engineering. We previously discovered that over activation of the Wnt signal transduction pathway by either lithium or Wnt3A stimulates hMSC proliferation while retaining pluripotency. Release of Wnt3A or lithium from porous calcium phosphate scaffolds, which we use for bone tissue engineering, could provide a mitogenic stimulus to implanted hMSCs. To define the proper release profile, we first assessed the effect of Wnt over activation on osteogenic differentiation of hMSCs. Here, we report that both lithium and Wnt3A strongly inhibit dexamethasone-induced expression of the osteogenic marker alkaline phosphatase (ALP). Moreover, lithium partly inhibited mineralization of hMSCs whereas Wnt3A completely blocked it. Time course analysis during osteogenic differentiation revealed that 4 days of Wnt3A exposure before the onset of mineralization is sufficient to block mineralization completely. Gene expression profiling in Wnt3A and lithium-exposed hMSCs showed that many osteogenic and chondrogenic markers, normally expressed in proliferating hMSCs, are downregulated upon Wnt stimulation. We conclude that Wnt signaling inhibits dexamethasone-induced osteogenesis in hMSCs. In future studies, we will try to limit release of lithium or Wnt3A from calcium phosphate scaffolds to the proliferative phase of osteogenesis.
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              Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification.

              Andria Culbert, Salin A. Chakkalakal, Edwin Theosmy … (2014)
              Bone morphogenetic protein (BMP) signaling is a critical regulator of cartilage differentiation and endochondral ossification. Gain-of-function mutations in ALK2, a type I BMP receptor, cause the debilitating disorder fibrodysplasia ossificans progressiva (FOP) and result in progressive heterotopic (extraskeletal) endochondral ossification within soft connective tissues. Here, we used murine mesenchymal progenitor cells to investigate the contribution of Alk2 during chondrogenic differentiation and heterotopic endochondral ossification (HEO). Alk2(R206H/+) (gain-of-function), Alk2(CKO) (loss-of-function), and wild-type mouse embryonic fibroblasts were evaluated for chondrogenic potential. Chondrogenic differentiation was accelerated in Alk2(R206H/+) cells, due in part to enhanced sensitivity to BMP ligand. In vivo, Alk2(R206H/+) cells initiated robust HEO and recruited wild-type cell contribution. Despite expression of other type I BMP receptors (Alk3 and Alk6), chondrogenesis of Alk2(CKO) cells was severely impaired by absence of Alk2 during early differentiation. Alk2 is therefore a direct regulator of cartilage formation and mediates chondrogenic commitment of progenitor cells. These data establish that at least one effect of ALK2 gain-of-function mutations in FOP patients is enhanced chondrogenic differentiation which supports formation of heterotopic endochondral bone. This establishes ALK2 as a plausible therapeutic target during early chondrogenic stages of lesion formation for preventing heterotopic bone formation in FOP and other conditions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Exp Ther Med
                Journal ID (iso-abbrev): Exp Ther Med
                Journal ID (publisher-id): ETM
                Title: Experimental and Therapeutic Medicine
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-0981
                ISSN (Electronic): 1792-1015
                Publication date (Print): December 2017
                Publication date (Electronic): 27 September 2017
                Publication date PMC-release: 27 September 2017
                Volume: 14
                Issue: 6
                Pages: 5424-5428
                Affiliations
                [1 ]Immunization Section, Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, P.R. China
                [2 ]Department of Orthopedics, The Affiliated People's Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, P.R. China
                [3 ]Department of Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010030, P.R. China
                Author notes
                Correspondence to: Dr Dai-He Li, Department of Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, 1 Yingfangdao Street, Hohhot, Inner Mongolia 010030, P.R. China, E-mail: daiheli1122@ 123456126.com
                Article
                Publisher ID: ETM-0-0-5210
                DOI: 10.3892/etm.2017.5210
                PMC ID: 5740575
                PubMed ID: 29285071
                SO-VID: 359a2935-d0c6-473b-8173-846b8bb1fa5c
                Copyright © Copyright: © Fu et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 13 February 2016
                Date accepted : 17 February 2017
                Categories
                Subject: Articles

                ScienceOpen disciplines: Medicine
                Keywords: rabbit mesenchymal stem cells,bone morphogenetic protein-7,differentiation,wnt/β-catenin,cartilage
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: rabbit mesenchymal stem cells, bone morphogenetic protein-7, differentiation, wnt/β-catenin, cartilage

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