Immunohistochemical localization of bone morphogenetic proteins (BMPs) 2, 4, 6, and 7 during induced heterotopic bone formation

McCullough, Kirk A.; Waits, Chad; Garimella, Rama Murthy; Tague, Sarah E.; Sipe, Joseph B.; Anderson, H. Clarke

doi:10.1002/jor.20340

Cited by 34 publications

(31 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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“…The mechanism of osteoclast-mediated osteoblastic bone formation is not well understood. Bone anabolic factors that have so far been reported in osteoclasts include TGF-b (Robinson et al 1996), IGF-1 (Hayden et al 1995), IL-6 (Sims et al 2004), and BMPs (Anderson et al 2000;Dhanyamraju et al 2003;Garimella et al 2006;McCullough et al 2007). Of these, only BMPs are known to be capable of inducing new bone formation (Wozney and Rosen 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Only recently, a more direct anabolic role of osteoclasts in stimulating bone formation has been indicated, in which osteoclasts secrete anabolic growth factors that mediate osteoblast chemotaxis, proliferation, differentiation, and mineralization (Koh et al 2005;Martin and Sims 2005;Henriksen et al 2006;Karsdal et al 2007). Some of the osteoclast-secreted factors that may enhance osteoblast activity include TGF-b (Robinson et al 1996), IGF-1 (Hayden et al 1995), TRAP (tartrate-resistant acid phosphatase) (Sheu et al 2002(Sheu et al ,2003, and BMPs (Anderson et al 2000;Dhanyamraju et al 2003;Garimella et al 2006;McCullough et al 2007). BMPs are members of the TGF-b superfamily that have highly conserved seven-cysteine repeats in their carboxy terminus (Wozney 1992).…”

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confidence: 99%

Expression and Synthesis of Bone Morphogenetic Proteins by Osteoclasts: A Possible Path to Anabolic Bone Remodeling

Garimella

Tague

Zhang

et al. 2008

J Histochem Cytochem.

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Skeletal remodeling is a finely orchestrated process coupling bone formation to bone resorption. The dynamics of coupling is regulated by the microenvironment at the bone remodeling site, which in turn is influenced by the intercellular communication between cells like osteoclasts and osteoblasts. Understanding the dynamics of coupling is important in devising new therapeutic approaches to the treatment of skeletal diseases characterized by disturbances in the bone remodeling process. In this study, we report the localization of bone morphogenetic proteins (BMPs) in osteoclasts generated from primary cocultures of bone marrow cells from mouse femur and tibia with mouse calvarial osteoblasts, using immunocytochemistry and in situ hybridization. Positive staining was seen in osteoclasts for BMP-2, -4, -6, and -7. Real-time PCR was used to quantitatively confirm the expression of transcripts for BMP-2, BMP-4, and BMP-6 mRNA in murine osteoclasts. Finally, the presence of BMP-2, -4, -6, and-7 proteins was confirmed in osteoclast lysates by Western blotting. Overall, our data suggest a possible direct role for osteoclasts in promoting bone formation via expression and synthesis of BMPs, which then would play an important role in promoting the recruitment, proliferation, and differentiation of osteoblasts at bone resorption sites.

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“…The bone morphogenetic proteins (BMPs) might be potential candidates [7]. BMPs act in combination with LIF to sustain self-renewal and preserve the multilineage differentiation capacity of ESCs.…”

Section: Dear Editormentioning

confidence: 99%

Long-term survival of exogenous embryonic stem cells in adult bone marrow

Liu

et al. 2011

Cell Res

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Immunohistochemical localization of bone morphogenetic proteins (BMPs) 2, 4, 6, and 7 during induced heterotopic bone formation

Cited by 34 publications

References 41 publications

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

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

Expression and Synthesis of Bone Morphogenetic Proteins by Osteoclasts: A Possible Path to Anabolic Bone Remodeling

Long-term survival of exogenous embryonic stem cells in adult bone marrow

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