Nuclear variants of bone morphogenetic proteins

Felin, Jenny E.; Mayo, Jaime L.; Loos, Trina J; Jensen, Jordan D.; Sperry, Daniel K; Gaufin, Stephanie L; Meinhart, Christopher A; Moss, Jennie B.; Bridgewater, Laura C.

doi:10.1186/1471-2121-11-20

Cited by 26 publications

(34 citation statements)

References 48 publications

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“…To determine whether mutation of this portion of the NLS was sufficient to prevent nuclear localization, we constructed a mutant BMP2/GFP expression plasmid (called RKRmBmp2/GFP) in which RKR was replaced with AAA and transfected it into cultured cells. This mutation eliminated nuclear localization of the GFP-tagged BMP2 in cultured RCS cells just like the previously described KR RKR to AA AAA mutation did [20]. To determine whether BMP2 growth factor containing this mutation could still be secreted, an HA-tagged RKRmBmp2 expression vector (RKRmBmp2/HA) was transfected into cultured RCS cells and culture medium was collected 48 hrs later.…”

Section: Resultsmentioning

confidence: 92%

A Novel Bone Morphogenetic Protein 2 Mutant Mouse, , Displays Impaired Intracellular Handling in Skeletal Muscle

Bridgewater

Mayo

Evanson

et al. 2013

BioMed Research International

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We recently reported a novel form of BMP2, designated nBMP2, which is translated from an alternative downstream start codon and is localized to the nucleus rather than secreted from the cell. To examine the function of nBMP2 in the nucleus, we engineered a gene-targeted mutant mouse model (nBmp2NLStm) in which nBMP2 cannot be translocated to the nucleus. Immunohistochemistry demonstrated the presence of nBMP2 staining in the myonuclei of wild type but not mutant skeletal muscle. The nBmp2NLStm mouse exhibits altered function of skeletal muscle as demonstrated by a significant increase in the time required for relaxation following a stimulated twitch contraction. Force frequency analysis showed elevated force production in mutant muscles compared to controls from 10 to 60 Hz stimulation frequency, consistent with the mutant muscle's reduced ability to relax between rapidly stimulated contractions. Muscle relaxation after contraction is mediated by the active transport of Ca2+ from the cytoplasm to the sarcoplasmic reticulum by sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and enzyme activity assays revealed that SERCA activity in skeletal muscle from nBmp2NLStm mice was reduced to approximately 80% of wild type. These results suggest that nBMP2 plays a role in the establishment or maintenance of intracellular Ca2+ transport pathways in skeletal muscle.

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Section: Resultsmentioning

confidence: 92%

A Novel Bone Morphogenetic Protein 2 Mutant Mouse, , Displays Impaired Intracellular Handling in Skeletal Muscle

Bridgewater

Mayo

Evanson

et al. 2013

BioMed Research International

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“…In both blots, lane 1 and 2 were loaded with positive controls, while lane 3 – 6 were loaded with chick tissue samples. To understand the complicated patterns of BMP4 and BMP7 protein expression, it is important to note that monomers and dimers of the BMP proproteins and mature proteins, as well as other forms have been reported in published literature, a nd databases (in the public domain at http://www.uniprot.org/uniprot/Q90752), (Cui et al 2001; Felin et al 2010; Klosch et al 2005; Monroe et al 2000; Nelsen and Christian 2009). Masses corresponding to the different forms of BMP4 and BMP7 are listed in Table 2.…”

Section: Resultsmentioning

confidence: 99%

“…The choroid (lane 6) yielded only 2 bands, corresponding to the dimer of the proprotein (~ 90 kDa) and the monomer of mature BMP4 (~ 13 kDa; lane 1, which was loaded with commercial BMP4 protein, also showed single band at ~ 13 kDa). The RPE (lane 5) yielded the simplest pattern, with only one band, at ~ 40 kDa, which may represent a nuclear variant of BMP4 or mature BMP4, based on its molecular weight (Bessa et al 2009; Felin et al 2010; Klosch et al 2005). The pattern of BMP4 expression showed variability both between individual chicks and between the 3 ocular tissues analyzed, with one bird showing negligible choroidal expression of BMP4.…”

Section: Resultsmentioning

confidence: 99%

Effects of imposed defocus of opposite sign on temporal gene expression patterns of BMP4 and BMP7 in chick RPE

Zhang

Liu

et al. 2013

Experimental Eye Research

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This study investigated the effects of imposed optical defocus on the expression patterns of bone morphogenetic protein 4 and 7 (BMP4, BMP7) in chick retinal pigment epithelium (RPE), as indicators of roles in postnatal eye growth regulation. BMP4 and BMP7 gene and protein expression patterns were characterized for retina, RPE and choroid tissues of young normal White-Leghorn chickens. The effects of short-term (2 and 48 h) exposure to monocular +10 and −10 diopter (D) lenses on RPE gene expression of BMP4 and BMP7 were also examined. Tissues from both treated and fellow eyes as well as from eyes of age-matched untreated birds were included in the latter experiment. Of ocular tissues comprising the posterior wall of the chick eye, RPE showed the highest expression of BMP4 and BMP7 mRNA, compared to retina and choroid. Western blots and immunohistochemisty confirmed the expression of BMP4 and BMP7 protein in all layers - retina, RPE, choroid and sclera. With imposed defocus, both BMP4 and BMP7 showed bidirectional changes in expression in RPE, however, with different temporal patterns. With +10 D lenses, BMP4 gene expression was up-regulated after both 2 and 48 h of treatment, while BMP7 expression was up-regulated only after 48 h of lens wear. With −10 D lenses, both BMP4 and BMP7 showed down-regulation of gene expression for both 2 and 48 h treatment durations. With the −10 D lens treatment applied for 48 h, gene expression for both BMP4 and BMP7 was also down-regulated in contralateral fellows of treated eyes compared to eyes of untreated chicks. The rapid changes in gene expression in chick RPE observed for both BMP4 and BMP7, up or down according to the sign of imposed optical defocus, resemble similar trends reported for BMP2. Further studies are needed to confirm the roles of BMPs as ocular growth modulators, as suggested by these data. The data also suggest a role for the RPE as a conduit for relaying growth modulatory retinal signals.

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“…The timing and localization of BMP-2 are consistent with our current conclusions, which suggest that the activation of BMP-2 signaling in early progenitor cells is critical for the initiation of healing. While BMP-2 has been identified as a secreted factor that primarily functions as an autocrine and paracrine factor for cell proliferation and differentiation, a recent study demonstrates the existence of a nuclear variant of BMP-2 in the 10T1/2 mesenchymal cells and a rat chondrosarcoma (RCS) cell line, associated with cell cycle progression[36]. Although the study remained descriptive, it raises an interesting question as to a potential intracrine function of the nuclear variant of BMP-2 in modulating cellular proliferation, survival, and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing

Wang

Huang

Xue

et al. 2011

Bone

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Bone morphogenic protein 2 (BMP-2) plays a key role in skeletal development, repair and regeneration. To gain a better understanding of the role of BMP-2 in periosteum-mediated bone repair, we deleted BMP-2 postnatally at the initiation stage of healing utilizing a Tamoxifeninducible CreER mouse model. To mark the mutant cells, we further generated a BMP-2 f/f ; CreER; RosaR mouse model that enabled the activation of a LacZ reporter gene upon treatment of Tamoxifen. We demonstrated that deletion of BMP-2 at the onset of healing abolished periosteum-mediated bone/cartilage callus formation. In a chimeric periosteal callus with cells derived from both wild type and the mutant, over 90% of the mutant mesenchymal progenitors remained undifferentiated. Within differentiated bone and cartilage tissues, only a few cells could be identified as mutants. Using a bone graft transplantation approach, we further showed that transplantation of a mutant bone graft into a wild type host failed to rescue the deficient differentiation of the mutant cells at day 10 post-grafting. These data strongly suggest that the endogenous expression of BMP-2 plays a critical role in osteogenic and chondrogenic differentiation of periosteal progenitors during repair. To determine whether BMP-2 deficient cells remained responsive to exogenous BMP-2, we isolated periosteal mesenchymal progenitors from BMP-2 deficient bone autografts. The isolated cells demonstrated a 90% reduction of endogenous BMP-2 expression, accompanied by significant decrease in cellular proliferation and a near blockade of osteogenic differentiation. The addition of exogenous BMP-2 partially rescued impaired proliferation and further enhanced osteogenic differentiation in a dose dependent manner. Taken together, our data show that the initiation of the cortical bone repair in vivo is controlled by endogenous BMP-2. Future studies are necessary to determine the mechanisms by which the BMP-2 pathway is activated in periosteal progenitor cells at the onset of cortical bone repair.

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Nuclear variants of bone morphogenetic proteins

Cited by 26 publications

References 48 publications

A Novel Bone Morphogenetic Protein 2 Mutant Mouse, , Displays Impaired Intracellular Handling in Skeletal Muscle

A Novel Bone Morphogenetic Protein 2 Mutant Mouse, , Displays Impaired Intracellular Handling in Skeletal Muscle

Effects of imposed defocus of opposite sign on temporal gene expression patterns of BMP4 and BMP7 in chick RPE

Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing

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