Bone morphogenetic protein–2 activity is regulated by secreted phosphoprotein–24 kd, an extracellular pseudoreceptor, the gene for which maps to a region of the human genome important for bone quality

Brochmann, Elsa J.; Behnam, Keyvan; Murray, Samuel S.

doi:10.1016/j.metabol.2009.01.001

Cited by 21 publications

(21 citation statements)

References 59 publications

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“…15,16 It binds hydroxyapatite, 6,17 stimulates cathepsins, 18 and binds BMP-2 (Table 1) as well as BMP-7, GDF-5, and TGF-b (unpublished observations). Native spp24 inhibits bone formation, 8 whereas a 19 amino acid peptide based on the sequence of the BMP-binding region has been developed as a bone healing agent presumably based on a ''slow release'' (of BMP-2) mechanism.…”

Section: Discussionmentioning

confidence: 92%

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Brochmann

Simon²,

Jawien³

et al. 2010

Journal Orthopaedic Research

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Secreted phosphoprotein-24 kDa (spp24) is a bone morphogenetic protein (BMP)-binding protein isolated from bone. It exists in a number of size forms and is hypothesized to function as a BMP latency protein and/or a ''slow release'' mechanism for BMPs involved in bone turnover and repair. We have examined the hypothesis that proteolytic modification of the C-terminus of spp24 affects its BMP-2-binding properties and bioactivity in the BMP-2-stimulated ectopic bone forming bioassay. Three different size forms of recombinant spp24 that correspond to predicted 18.1 kDa, 16.0 kDa, and 14.5 kDa proteolytic products were compared to full-length (fl) spp24. One of these forms (spp18.1) we hypothesize to be the protein which Urist initially, but apparently inaccurately, called ''BMP.'' Only full-length spp24 completely inhibited BMP-2-induced bone formation. The 18.1 kDa truncated isoform of spp24 which we hypothesize to be Urist's protein did not. The inhibitory capacity of the proteins was correlated with their kinetic constants, assessed by surface plasmon resonance. At the highest, inhibitory, dose of spp24 and its derivatives, k d (''stability'') best predicted the extent of ectopic bone formation whereas at the lowest dose, which was not inhibitory, k a (''recognition'') best predicted the extent of ectopic bone formation. We conclude that proteolytic processing of spp24 affects the interaction of this protein with BMP-2 and this affects the function of the protein. ß

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Section: Discussionmentioning

confidence: 92%

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Brochmann

Simon²,

Jawien³

et al. 2010

Journal Orthopaedic Research

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“…Afp encodes an abundant serum protein specifically expressed in the VE (Dziadek and Adamson, 1978; Kwon et al, 2006). Secreted phosphoprotein 2 (also referred as SPP24) acts as a pseudoreceptor that regulates BMP activity (Brochmann et al, 2009), suggesting a negative feedback loop may operate upon BMP stimulation. Spp2 transcripts have been detected in the yolk sac (Hou et al, 2007), while Galectin-1 (LGALS1) is a β-galactoside binding lectin protein that regulates MAPK signaling in various cellular contexts (Brandt et al, 2010; Thijssen et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity

Artus

Douvaras

Piliszek

et al. 2012

Developmental Biology

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The visceral endoderm (VE) is an epithelial tissue in the early postimplantation mouse embryo that encapsulates the pluripotent epiblast distally and the extraembryonic ectoderm proximally. In addition to facilitating nutrient exchange before the establishment of a circulation, the VE is critical for patterning the epiblast. Since VE is derived from the primitive endoderm (PrE) of the blastocyst, and PrE-derived eXtraembryonic ENdoderm (XEN) cells can be propagated in vitro, XEN cells should provide an important tool for identifying factors that direct VE differentiation. In this study, we demonstrated that BMP4 signalling induces the formation of a polarized epithelium in XEN cells. This morphological transition was reversible, and was associated with the acquisition of a molecular signature comparable to extraembryonic (ex) VE. Resembling exVE which will form the endoderm of the visceral yolk sac, BMP4-treated XEN cells regulated hematopoiesis by stimulating the expansion of primitive erythroid progenitors. We also observed that LIF exerted an antagonistic effect on BMP4-induced XEN cell differentiation, thereby impacting the extrinsic conditions used for the isolation and maintenance of XEN cells in an undifferentiated state. Taken together, our data suggest that XEN cells can be differentiated towards an exVE identity upon BMP4 stimulation, and therefore represent a valuable tool for investigating PrE lineage differentiation.

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“…Extensive research has focused on BMP2’s ability to enable differentiation of precursor cells into osteoblasts and enhance osteoblast function[1]–[5]. BMP2 is highly expressed in osteoblasts [6]–[8], but little is known about how a deficiency of BMP2 affects differentiated osteogenic cells [9]–[11].…”

Section: Introductionmentioning

confidence: 99%

Long Bone Structure and Strength Depend on BMP2 from Osteoblasts and Osteocytes, but Not Vascular Endothelial Cells

et al. 2014

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The importance of bone morphogenetic protein 2 (BMP2) in the skeleton is well known. BMP2 is expressed in a variety of tissues during development, growth and healing. In this study we sought to better identify the role of tissue-specific BMP2 during post-natal growth and to determine if BMP2 knockout affects the ability of terminally differentiated cells to create high quality bone material. We targeted BMP2 knockout to two differentiated cell types known to express BMP2 during growth and healing, early-stage osteoblasts and their progeny (osterix promoted Cre) and vascular endothelial cells (vascular-endothelial-cadherin promoted Cre). Our objectives were to assess post-natal bone growth, structure and strength. We hypothesized that removal of BMP2 from osteogenic and vascular cells (separately) would result in smaller skeletons with inferior bone material properties. At 12 and 24 weeks of age the osteoblast knockout of BMP2 reduced body weight by 20%, but the vascular knockout had no effect. Analysis of bone in the tibia revealed reductions in cortical and cancellous bone size and volume in the osteoblast knockout, but not in the vascular endothelial knockout. Furthermore, forelimb strength testing revealed a 30% reduction in ultimate force at both 12 and 24 weeks in the osteoblast knockout of BMP2, but no change in the vascular endothelial knockout. Moreover, mechanical strength testing of femurs from osteoblast knockout mice demonstrated an increased Young’s modulus (greater than 35%) but decreased post-yield displacement (greater than 50%) at both 12 and 24 weeks of age. In summary, the osteoblast knockout of BMP2 reduced bone size and altered mechanical properties at the whole-bone and material levels. Osteoblast-derived BMP2 has an important role in post-natal skeletal growth, structure and strength, while vascular endothelial-derived BMP2 does not.

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Bone morphogenetic protein–2 activity is regulated by secreted phosphoprotein–24 kd, an extracellular pseudoreceptor, the gene for which maps to a region of the human genome important for bone quality

Cited by 21 publications

References 59 publications

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

Carboxy terminus of secreted phosphoprotein‐24 kDa (spp24) is essential for full inhibition of BMP‐2 activity

BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity

Long Bone Structure and Strength Depend on BMP2 from Osteoblasts and Osteocytes, but Not Vascular Endothelial Cells

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