Essential Requirement of BMPs-2/4 for Both Osteoblast and Osteoclast Formation in Murine Bone Marrow Cultures from Adult Mice: Antagonism by Noggin

Abe, Etsuko; Yamamoto, Masahide; Taguchi, Yasuto; Lecka‐Czernik, Beata; O’Brien, Charles A.; Economides, Aris N.; Stahl, Neil; Jilka, Robert L.; Manolagas, Stavros C.

doi:10.1359/jbmr.2000.15.4.663

Cited by 302 publications

(135 citation statements)

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“…Similar to observations by others, we also show moderate to intense expression of BMP2 and BMP7 in bone marrow cells, bone lining cells, osteoblasts, and osteocytes [40,41]. We observed a gradient of BMP7 expression, varying from intense staining at the endosteal side to no staining at the periosteal side of cortical bone.…”

Section: Discussionsupporting

confidence: 90%

“…However, the role of BMPs in bone remodeling is not fully understood. BMP2 is produced by bone marrow stromal cells and necessary for osteoblast differentiation [40,41]. Cheng and colleagues [42] reported an osteogenic hierarchy where BMPs 2, 6, and 9 are the most potent agents to induce osteoblast lineagespecific differentiation of mesenchymal progenitor cells, while most BMPs can promote the terminal differentiation of committed osteoblast precursors and osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

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Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

et al. 2011

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Bone mechanical adaptation is a cellular process that allows bones to adapt their mass and structure to mechanical loading. This process is governed by the osteocytes, which in response to mechanical loading produce signaling molecules that affect osteoblasts and osteoclasts. Bone morphogenic proteins (BMPs) are excellent candidates as signaling molecules, but it is unknown whether mechanically stimulated osteocytes affect bone adaptation through BMP production. Therefore, the aim of this study was to assess whether osteocytes produce BMPs in response to mechanical loading. In addition, since BMP7 has a vitamin D receptor (VDR) response element in the promoter region, we also investigated whether VDR is involved in the BMP7 response to mechanical loading. Human or VDR -/-mouse primary bone cells were submitted in vitro to 1 h pulsating fluid flow (PFF) and postincubated without PFF (PI) for 1-24 h, and gene and protein expression of BMP2 and BMP7 were quantified. In human bone cells, PFF did not change BMP2 gene expression, but it upregulated BMP7 gene expression by 4.4-to 5.6-fold at 1-3 h PI and stimulated BMP7 protein expression by 2.4-fold at 6 h PI. PFF did not stimulate BMP7 gene expression in VDR -/-mouse bone cells. These results show for the first time that mechanical loading upregulates BMP7, likely via the VDR, but not BMP2, gene and protein expression in osteocytes in vitro. Since BMP7 plays a major role in bone development and remodeling, these data might contribute to a better understanding of the mechanism leading to the mechanical adaptation of bone.Keywords Bone adaptation Á Bone morphogenic protein 2 Á Bone morphogenic protein 7 Á Osteocyte Á Mechanical loading Mechanical adaptation of bone is a cellular process that allows bones to adapt their mass and structure to their mechanical environment [1,2]. It is currently believed that this process of adaptation is governed by the osteocytes [3][4][5][6]. Osteocytes are terminally differentiated osteoblasts that become embedded deep within the mineralized bone matrix during bone formation. They are regularly distributed throughout the bone matrix and connected to each other by cytoplasmatic protrusions that run through the canaliculi [7]. This way the osteocytes form a unique dendritic network that enables contact not only with the bone surface but also with other cells [7]. When bones are loaded, the resulting deformation causes a flow of interstitial fluid through the lacunocanalicular network [8,9]. This flow of fluid results in mechanical stimulation of the osteocytes [6,8,9]. The mechanically stimulated osteocytes then produce signaling molecules that are potent regulators of the other types of bone cells, i.e., osteoblastsThe authors have stated that they have no conflict of interest.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

et al. 2011

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“…In the presence of inflammation, BMP2 enhances bone resorption via upregulation of COX-2 and RANKL in osteoblasts [92]. In line with this, Noggin , a BMP antagonist, prevents osteoclastogenesis in cultures of the bone marrow [93]. Osteoclasts isolated from long bones, in the presence of RANKL, increased resorption by BMP2 via cathepsin K and carbonic anhydrase II [77].…”

Section: In the Presence Of Coupled Bone Cells Bmps Stimulate Resorptionmentioning

confidence: 84%

“…In contrast, BMP5 and -6 activated osteoclasts in a biphasic mode, depending on the RANKL/ OPG mRNA ratio and the BMP concentration [96]. Mechanistically, BMP2 transcriptionally regulates both RANKL [92,93] and CSF-1 [97], which are critical factors for osteoblastinduced osteoclastogenesis. It is suggested that BMP2 and -7 regulate the osteoclast activity both via OPG-RANKL system and through upregulating the expression of GM-CSF, stromal cell-derived factor-1 (SCF1) and resorption enzymes.…”

Section: In the Presence Of Coupled Bone Cells Bmps Stimulate Resorptionmentioning

confidence: 99%

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

Vukičević

Oppermann

Verbanac

et al. 2013

International Orthopaedics (SICOT)

105

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Purpose The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW. Methods Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/-mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.Results Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of Mladenka Jurin contributed equally to this paper. S. Vukicevic (*) : J. Curak : J. Brkljacic : M. Pauk : I. Erjavec : I. Dumic-Cule : R. Novak : V. Kufner : T. Bordukalo Niksic :

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“…We found the opposite in this study, which suggests that BMP2 may also be involved in regulating periosteal bone resorption. In recent years, studies have in fact found that BMP2 can enhance osteoclastogenesis indirectly by stimulating osteoblasts or stromal cells to produce osteoclast-promoting factors, such as RANKL (Abe et al, 2000;Otsuka et al, 2003), or directly by activating osteoclast differentiation in the presence of RANKL (Jensen et al, 2009). It is hence likely that stronger expression of BMP2 at the anterior periosteal region plays an assisting role in promoting osteoclastogenesis by synergizing with RANKL.…”

Section: Discussionmentioning

confidence: 99%

Molecular Variations Related to the Regional Differences in Periosteal Growth at the Mandibular Ramus

Sun

Tee

2010

The Anatomical Record

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Periosteal growth at human mandibular ramus is characterized by bone apposition at the posterior border and resorption at the anterior border. Molecular control of this regional variation is unclear. This study examined the expression of several molecules involved in bone apposition/ resorption at these regions in vivo and in vitro. By using growing pigs as a model, the periosteal growth was assessed at the mandibular ramus by vital staining and histological observations. In parallel, periosteal tissues were harvested and pulverized for RNA and protein extraction. Periosteal cells were also isolated, expanded in osteogenic media, and subjected to a single dose of dynamic tensile strain (0, 5, or 10% magnitude at 0.5 Hz) to examine their responses to mechanical loading. Real-time RT-PCR and Western blot analyses were used to examine mRNA and protein expression from periosteal tissues and cultured cells. Histological observation confirmed an anterior-resorption/posterior-apposition pattern in the pig mandibular ramus. Both in vivo tissue and in vitro cells demonstrated greater mRNA expression of receptor activator of NF-jB ligand (RANKL)/osteoprotegerin (OPG) ratio and bone morphogenetic protein 2 (BMP2) at the anterior region, while OPG expression at the anterior region was lower than the posterior region. In response to the application of a single dose of dynamic tensile strain, cultured periosteal cells appeared to change the expression profile of osteogenic markers but not that of RANKL/OPG and BMP2. These findings suggest that the unique regional variation of periosteal activity at the mandibular ramus is regulated by a differential expression of RANKL/OPG ratio (likely through differential induction of OPG) and BMP2. Anat Rec, 294:79-87, 2011. V V C 2010 Wiley-Liss, Inc.Key words: periosteum; mandibular growth; RANKL/OPG; tissue engineering; cell loadingHuman mandibular growth is mainly through endochondral bone formation at the condyles and intramembranous bone formation at the periosteum (Enlow and Hans, 1996). While condylar growth provides the overall elongation and rotation of the mandible (Bjork and Skieller, 1983), periosteal activity causes extensive surface modeling/remodeling or reshaping of the mandible (Enlow and Hans, 1996). One striking feature of mandibular periosteal activity is at the ramus, where bone resorption takes place at the anterior (rostral) border whereas bone apposition at the posterior (caudal) border (Robinson and Sarnat, 1955;Seiton and Engel, 1969;Hans et al., 1995). At the cell level, osteogenic proliferation is concentrated at the appositional posterior ramal region, whereas osteoclasts are mainly present at the resorptive anterior region (Ochareon and Herring, 2007). However, the molecular mechanisms related to these differential periosteal activities are mostly unknown.

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Essential Requirement of BMPs-2/4 for Both Osteoblast and Osteoclast Formation in Murine Bone Marrow Cultures from Adult Mice: Antagonism by Noggin

Cited by 302 publications

References 35 publications

Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

Molecular Variations Related to the Regional Differences in Periosteal Growth at the Mandibular Ramus

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