Stimulatory effect of bone morphogenetic protein-2 on osteoclast-like cell formation and bone-resorbing activity

Kanatani, Masanori; Sugimoto, Toshitsugu; Kaji, Hiroshi; Kobayashi, Tatsuya; Nishiyama, Keisuke; Fukase, Masaaki; Kumegawa, Masayoshi; Chihara, Kazuo

doi:10.1002/jbmr.5650101110

Cited by 209 publications

(116 citation statements)

References 40 publications

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“…The change of some soluble factors in the serum of this patient by glucocorticoid use and immobilization might be responsible for enhancing the level of ALP, OCN and BMP-2 in osteoblast. Furthermore, increased bone resorption indices may be due to BMP-2, stimulation of bone resorption by enhanced osteoclast formation, and osteoclastic activity [14,15]. Okamoto et al [16] reported that mice overexpressing BMP-4 in bone developed severe osteopenia with increased osteoclast number.…”

Section: Discussionmentioning

confidence: 99%

Effects of Serum from a Fibrodysplasia Ossificans Progressiva Patient on Osteoblastic Cells

Hisa¹,

Kawara²,

Katagiri³

et al. 2012

OJEMD

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Introduction: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. Patients and Methods: In the present study, we present a case of FOP with marked progressive ossification of extraskeletal tissues. We investigated whether soluble factors in serum would affect the osteoblast phenotype by examining the effects of serum from this patient and control subjects on mouse osteoblastic MC3T3-E1 cells. Results: The clinical findings of this patient were compatible with FOP, and direct sequence analysis of genomic DNA demonstrated the presence of a heterozygous 617G > A (R206H) mutation of activin type 1 receptor (ACVR1). Serum from the FOP patient enhanced the level of alkaline phosphatase (ALP) in Western blotting, compared with serum from the control, in MC3T3-E1 cells. Moreover, serum from the FOP patient enhanced the levels of ALP, osteocalcin and bone morphogenetic protein-2 mRNA in these cells. Conclusion: We presented a case of FOP with progressive ossification in extra-skeletal tissues with ACVR1 mutation. The present data suggest that the serum from this patient includes some soluble factors, which might enhance the osteoblast differentiation and BMP-2 expression in mouse osteoblastic cells.

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Section: Discussionmentioning

confidence: 99%

Effects of Serum from a Fibrodysplasia Ossificans Progressiva Patient on Osteoblastic Cells

Hisa¹,

Kawara²,

Katagiri³

et al. 2012

OJEMD

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“…BMPs are differentiating paracrine proteins acting on a variety of cells in bone remodeling, not only bone forming cells but also osteoclasts. 6,15 In the chamber, the results of the osteoclast activity can clearly be seen as the ingrowth front sweeps into the dead graft ( Fig. 2A,B).…”

Section: Manipulating Responses In Bone Graft Remodelingmentioning

confidence: 94%

“…However, resorption can also be increased. 6,7 In bone chambers, BMPs increase bone ingrowth rate in nonvital bone grafts, but also cause an almost simultaneous resorption of newly formed bone. 8 The combination of a local bisphosphonate (clodronate) and BMP-7 caused both increased ingrowth and increased bone density in impacted grafts in the bone conduction chamber model.…”

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confidence: 99%

Manipulating the anabolic and catabolic response in bone graft remodeling: Synergism by a combination of local BMP‐7 and a single systemic dosis of zoledronate

Harding

Aspenberg

Kataoka

et al. 2008

Journal Orthopaedic Research

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Remodeling of a bone graft can be influenced both by anabolic substances, such as a bone morphogenic protein (BMP) and by anticatabolic substances, such as the bisphosphonates. BMPs are potent bone anabolic substances, but also boost catabolism and cause resorption. Bisphosphonates inhibit osteoclast function and can be used to postpone resorption. In the present study a combination of both drugs was explored in a rat bone chamber model. Cancellous bone grafts were treated with either BMP-7 or saline and placed in a bone chamber implanted in the proximal tibia. After 2 weeks, an injection of either zoledronate 0.1 mg/kg or saline was given subcutaneously. The rats were killed after 6 weeks, and bone ingrowth distance into the graft and graft resorption were measured by histomorphometry. BMP-7 significantly (p ¼ 0.007) increased new bone ingrowth distance into the graft from 2.0 mm (SD ¼ 0.98 mm) in the controls to 3.1 mm (SD ¼ 0.93 mm). If bisphosphonate was not given, most of the newly formed and old graft bone was resorbed. A single injection of zoledronate significantly (p < 0.001) increased the trabecular volume/total volume to 40% (SD ¼ 9%) compared to 14% (SD ¼ 10%) in the nonbisphosphonate treated. In total, the net amount of bone increased by 400% when BMP-7 and zoledronate combined was compared to saline. A bone graft can be treated with BMP-7 to increase new bone formation and at the same time be protected against premature catabolism by a single dose of a bisphosphonate. This combination might be useful in various conditions in orthopedic reconstruction. Healing and normal physiological skeletal repair involve a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone at the disease or injury site. These pathways are mediated by a number of effector cells, primarily the catabolic bone-resorbing osteoclasts and the anabolic bone-forming osteoblasts, which produce new bone tissue to restore skeletal integrity. A balance between them is required for normal fracture repair and bone graft remodeling. Delayed healing or non-union can be a failure of the anabolic response, an increased or premature catabolic response, or sometimes both. 1 The anabolic and catabolic responses can be manipulated with pharmaceuticals, and in the bone conduction chamber, 2 we can study how drugs, separately or in combinations, influence bone formation and resorption.Bisphosphonates reduce osteoclastic catabolic activity in experimental studies. Circulating bisphosphonates bind to bone mineral, and, when the bone is resorbed by osteoclasts, bisphosphonates are internalized and interfere with cell metabolism leading to osteoclast apoptosis. 3 Systemic bisphosphonate treatment can postpone resorption of a bone graft. 4 In fractures, postponing the catabolic response and in consequence the resorption of the new-forming callus, leads to a stronger callus. 5 Bone morphogenic proteins (BMPs) bind to specific cell receptors, starting a signaling cascade that l...

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“…In culture, human monocytes chemotactically respond to BMP4 [87], while BMP7 stimulates the formation of TRAP positive mononuclear cells which, in the presence of 1,25(OH) 2 D 3 , mature and resorb bone [88,89]. BMP2 also mediates the osteoblast-osteoclast interaction, and in the presence of bone marrow stromal cells supports the maturation of mononuclear cells and bone resorption [90,91]. In the presence of inflammation, BMP2 enhances bone resorption via upregulation of COX-2 and RANKL in osteoblasts [92].…”

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)

102

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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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Stimulatory effect of bone morphogenetic protein-2 on osteoclast-like cell formation and bone-resorbing activity

Cited by 209 publications

References 40 publications

Effects of Serum from a Fibrodysplasia Ossificans Progressiva Patient on Osteoblastic Cells

Effects of Serum from a Fibrodysplasia Ossificans Progressiva Patient on Osteoblastic Cells

Manipulating the anabolic and catabolic response in bone graft remodeling: Synergism by a combination of local BMP‐7 and a single systemic dosis of zoledronate

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

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