International Orthopaedics

, Volume 42, Issue 11, pp 2619–2626 | Cite as

Bone morphogenetic proteins in fracture repair

  • Ivo Dumic-Cule
  • Mihaela Peric
  • Lucija Kucko
  • Lovorka Grgurevic
  • Marko Pecina
  • Slobodan VukicevicEmail author
Open Access
Review Article


Bone fractures represent a significant medical morbidity among aged population with osteoporosis. Bone morphogenetic proteins (BMPs) are suggested to have therapeutic potential to enhance fracture healing in such patients. Though BMP-mediated fracture healing has been well-documented in preclinical models, there has been no clinical study that demonstrated unequivocally that indeed a BMP when presented with an appropriate scaffold could provide basis for robust outcome for delayed or non-union diaphyseal bone fractures. This review presents a comprehensive insight towards the existing knowledge on the role of BMP signaling in bone formation and maintenance. Also therapeutic options based on BMP biology are discussed.

A novel osteoinductive autologous bone graft substitute (ABGS) aimed to accelerate bone regeneration was developed and is currently being tested in the clinical setting. It comprises of a biologically compatible autologous carrier made from the patient’s peripheral blood (autologous blood coagulum, ABC) and of rhBMP6 as an active ingredient. Such formulation circumvents the use of animal-derived materials, significantly limits inflammatory processes common in commercial bone devices and renders the carrier flexible, malleable, and injectable ensuring the ease of use. The ongoing clinical trials result will provide more detailed insights into the safety, tolerability, pharmacokinetics, and bone healing effects in humans and potentially provide novel and safe therapeutic options for bone repair.


Bone Bone fracture Bone morphogenetic proteins Regenerative treatment BMP6 containing osteogenic device 


Bone is one of the few tissues in the adult human body with the ability to repair, regenerate, and restore function spontaneously upon fracture. In the EU, 3.5 million bone fractures were reported in 2010 [1] and it is estimated that more than 50 million men and women will be at bone fracture risk due to osteopenia/osteoporosis in 2050 [2].

Bone fracture repair

Bone healing process is a prototype for tissue engineering since it involves signal, cells and substratum, and is traditionally divided into three stages: an early inflammatory and cell recruitment stage (callus formation), intermittent cell differentiation and formation of new bone (fracture repair) and late bone remodeling and formation of defined cortices (restoration). Most of the fractures heal in time without any consequences, however, when fractures are compounded or open it can result in indirect or secondary healing due to incomplete mechanical stability of broken fragments in mixed intramembranous and endochondral ossification subsequent to callus formation. Intramembranous ossification produces bone directly under the periosteum within the first days after injury, overleaping chondrogenesis in the centre leading to endochondral ossification. Improper osseous healing has potentially devastating consequences, ranging from disfigurement to the loss of function and eventually loss of limb. In cases where normal bone fracture healing is not achieved, it is advisable to apply BMP containing substratum to induce the formation of new bone locally and assure the bridging [3]. In order to achieve successful bone union adequate blood supply, aseptic environment, mechanical stability, and appropriate soft tissue management are mandatory as well. There are reports indicating a genetic predisposition for bone non-union, where defective BMP downstream signaling correlated with non-union fractures [4]. In approximately 10% of cases, fractured bones heal slowly (mal-union) or fail to heal (non-union) and they require additional medical interventions to repair the fracture, like in smokers and steroid users [3]. The conditions that predispose fractured bone to impaired healing include old age [5] and smoking [6], as well as other conditions with malfunction in bone metabolism, like osteoporosis, diabetes, and NSAID use [7, 8].

Bone morphogenetic proteins

Bone morphogenetic proteins (BMPs) are growth and differentiation factors and form a large subfamily of the transforming growth factor-beta (TGF-β) superfamily. They provide morphogenetic signals for skeletal development during embryogenesis and are responsible for adult fracture healing by recapitulating a cascade of cellular events associated with embryonic bone formation. More than 30 different BMPs based on structural similarity have been identified and some of them were suggested to play a role beyond bone [9, 10, 11]. Bone-inducing BMPs are divided into several subgroups, based on the homology of their amino acid sequences: BMP2/BMP4, BMP5/BMP6/BMP7, BMP9/BMP10, and BMP12/BMP13/BMP14 groups, while other BMPs do not have proven osteogenic properties [10].

In 1965, Marshall Urist demonstrated for the first time that demineralized bone has capacity to induce new bone when implanted at ectopic sites, which he described as “bone formation by auto induction” [12, 13]. Reddi has shown that implantation of demineralized bone matrix induces a cascade of cellular events involving mesenchymal cell recruitment, proliferation, and differentiation into cartilage-forming cells. With concurrent invasion of blood vessels, cartilage undergoes hypertrophy resulting in formation of new bone and bone marrow elements [14]. It is known that the process of ectopic bone formation stimulated by BMPs is mediated by progenitor cells found around blood vessels and connective tissues without the presence of osteoclasts [15]. Namely, a biological response to BMPs is dependent on the local microenvironment and type of cells present at the site of BMP implantation. BMPs are more effective in abundancy of pluripotential cells. In bone injuries, skeletal progenitor cells originate from multiple tissue compartments including the injured periosteum, endosteum, vascular tissue, and the surrounding musculature, and jointly contribute to skeletal healing [16]. Periosteal bone and the microenvironment outside the bone medullar cavity both lack osteoclasts and, therefore, uncoupled osteoblast precursor cells upon addition of a BMP on an appropriate carrier together form bone [15]. However, during bone remodeling coupling between osteoblasts and osteoclasts occurs in bone shaft, representing a crucial step in bone remodeling that depends on the local milieu of cytokine signaling and systemic hormones.

Currently, effects of BMPs are described after local implantation. It was shown that high levels of circulating BMP9 seem to be associated with faster fracture healing, but results were not significant [17]. Moreover, there was no difference between other measured BMPs in groups with normal and delayed healing. Plasma BMP values were determined in a single time-point, thus disabling the insight into potential difference between healing phases.

Molecular interventions into BMP bone development and growth

It was long thought that BMPs primarily induce new bone at an endosteal bone site. However, recent studies have shown that the inactivation of the BMPR-IA receptor signaling in mouse osteoblasts leads to significantly increased bone volume [18]. Correspondingly, when a conditional deletion of the same receptor in differentiated mouse osteoclasts was introduced, an increase in the osteoblastic bone formation and bone volume was demonstrated [19]. These scientists also showed that BMP4 overexpression in mouse osteoblasts resulted in bone loss [20]. When BMP2 was used intramedullary at an endosteal bone site, a suppression of osteogenesis was observed and explained to be due to downregulation of Runx2 and collagen I synthesis [21]. Additionally, inhibition of Wnt signaling occurs as a consequence of targeting Wnt inhibitors Dkk1 and Sost downstream of BMP signaling through BMPR-IA receptor in osteoblasts [22]. The observed BMP effect on endosteal bone cells is the result of a pronounced activation of osteoclasts and their progenitors and expression of BMPR-IA and BMPR-II receptors on their membranes [15]. The sum effect of osteogenic BMPs seems to be a net bone loss, resulting from their stronger effect on osteoclasts compared to osteoblasts. This was supported by the rat study showing superiority in treating fracture non-union with early endothelial progenitor cells, when compared to late endothelial progenitor cells which release more BMP2 [23]. These unexpected results are inconsistent with the in vitro evidence showing that BMP2 and 7 promote differentiation of various osteoblast-like cells and in vivo induce new bone formation at ectopic sites in experimental animals (Fig. 1). On the other hand, when BMP2 and 7 are applied at orthotopic bone sites bone repair will depend on the presence of coupled bone cells and on the bone microenvironment and the result of therapy will be the loss of the bone volume. However, when osteogenic growth factors are delivered at an ectopic site in an uncoupled cell environment or in the vicinity of the periosteum or muscle, they will support bone formation and bone healing by extending the area of new bone from an uncoupled to a coupled bone surface, which will then incorporate into an endogenous coupled bone microenvironment.
Fig. 1

Different responses of rhBMPs on bone endosteal, periosteal, and muscle compartments. At the endosteal bone surface, BMP affects bone resorption and formation resulting in downregulation of Runx2, collagen type I, and Wnt signaling. At the periosteal surface BMPs upregulate the expression of Id genes in surrounding muscles which results in endochondral bone formation spreading from the bone surface into the medullary canal. They also stimulate differentiation of periosteum progenitor cells into osteoblasts

In the presence of calcium phosphate-based biomaterials, BMP, Wnt, and PKC signaling pathways are activated discriminating the bone forming from non-bone-forming constructs [24] which additionally influences the quality of newly formed bone.

BMPs and physiological bone repair

Fracture healing recapitulates events that occur during embryonic bone formation, and indicates that the cells and pattern defining molecules that drive bone formation during embryogenesis are still present in the adult bone. Bone healing process is traditionally divided into three stages: an early inflammatory stage, a repair stage, and a late remodeling [25]. Most of the fractures undergo indirect or secondary healing due to incomplete stability of broken fragments resulting in mixed intramembranous and endochondral ossification and subsequent callus formation. Intramembranous ossification produces bone directly under the periosteum within the first days after injury, overlapping chondrogenesis which is the main step in endochondral ossification. BMP 2, 4, and 7 are highly upregulated in this early stage around the injured periosteum. Role of BMP signaling in both intramembranous and endochondral ossification was suggested two decades ago [26]. This early phase of healing enables temporarily fracture stabilization and further endochondral bone formation. It is characterized by the recruitment of mesenchymal stem cells (MSC) and successive chondrogenesis resulting in soft callus formation [27]. BMPs potentiate differentiation of MSC towards chondroblast and osteoblast lineage. It was demonstrated in the mouse fracture healing studies that BMP2 initiates the repair cascade with its mRNA expression peaking at 24 h after bone injury [28]. In the mouse MSCs differentiation experiments, BMP2 regulated the expression of several other BMPs and was crucial for the successful differentiation of MSCs into osteoblasts [29]. BMP3, 4, 7, and 8 are expressed in the osteogenic stage of bone repair, when the resorption of calcified cartilage, osteoblastic recruitment, and bone formation are most pronounced. BMP5 and BMP6 are constitutively expressed from days three to 21 during fracture healing in mice, suggesting their active role in both intramembranous and endochondral ossification. Although BMP8 has a high osteogenic potential, BMP2, BMP6, and BMP9 are the most potent inducers of MSCs differentiation to osteoblasts, while other BMPs mainly stimulate the maturation of osteoblasts [30]. In the presence of adequate angiogenesis during the late phase of healing, cartilage tissue is replaced by the woven bone, which undergoes remodeling to potentiate normal function of the healed bone.

Complex interactions between osteoblasts and osteoclasts result in bone remodeling and take place at particular sites throughout the fracture called bone metabolic unit (BMU). Effects of BMP signaling on osteoblasts mostly depend on the maturation stage: BMPs enhance their early phase, while have little or no influence on mature osteoblasts [31]. BMP2, 4, and 7 were detected by immunostaining in osteoclast-like cells in the newly formed trabecular bone, mostly between days 14 and 28 after fracture [32].

Chemotactic signal for osteoprogenitors is provided by numerous growth factors, among which bone morphogenetic proteins (BMPs) have the central role. Integrin-linked kinase was shown to have huge impact in modeling cytoskeletal organization and adjusting BMP signaling in osteoprogenitor cells [33]. Mice lacking functional integrin-linked kinase in osterix-expressing cells displayed a significantly reduced trabecular bone mass after five weeks, which persisted into adulthood.

Expression of BMP signaling components in fractures

As BMP signaling pathways emerged as mainstay of successful fracture healing, potential clinical application of BMP antagonists in bone repair was proposed [34]. Kloen and collaborators were the first to report BMP signaling in human callus obtained from patients with complicated fracture who underwent a surgical procedure [35]. Immunohistochemical analyses revealed an increased staining for BMP2 and 4 in the area of endochondral ossification, particularly in the matrix between the newly formed osteoid. In contrast, BMP3 and 7 were greatly expressed in osteoblasts inside the novel osteoid tissue. Osteoclasts did not exhibit significant expression of BMPs, except BMP3, which is generally considered to be an antagonist of regular BMP effects. BMPR-IA and BMPR-IB were present in all cells of interest, mainly fibroblasts, osteoblasts, chondroblasts, and osteoclasts, while BMPR-II staining was less intense in osteoblasts and cartilaginous tissue. Further studies scrutinized expression of BMP inhibitors in fracture callus [36]. Inhibition of Noggin and Chordin increased the osteogenic differentiation of murine and human mesenchymal stem cells [37]. The expression of BMP2, BMP4, Noggin, and Chordin in healing tissue was highlighted in the areas of endochondral ossification, confirming the central role of BMP signaling in this phase of bone repair. Namely, their expression was only moderate in initial and remodeling phase. BMP14 demonstrated the strongest staining in human fractures consistent with its inhibition of long bone healing in mice resulting from the delay of chondrocyte differentiation [38]. Concept of impaired healing and subsequent non-union because of the imbalance between BMPs and their antagonists have been introduced by Reddi and colleagues [39]. However, expression of Noggin and Chordin was similar in patients with non-unions and normal bone healing [40].

Recent study using human tissue confirmed distortion in expression of BMPs and BMP inhibitors in a non-union, when compared to the normal fracture healing [41]. In non-unions, the chondrocyte expression of BMP2 was significantly decreased, and BMP7 was completely absent, while mature osteoblasts exhibited normal expression of BMPs maintaining the expression of BMP inhibitors similar in both osteoblasts and chondrocytes. This imbalance hypothesis would therefore be supported mainly by the lack of BMP expression in cartilage tissue and impossibility to contribute to osteoblastic differentiation and subsequent ossification.

Additional clinical trials and carefully designed animal experiments including knockout mice and specific inhibition of BMP antagonists are necessary for clarification whether a bone non-union is a consequence of increased BMP antagonists’ concentration and insufficient BMP levels.

BMP-based therapy for fracture healing

Following FDA approval for specific indications in 2002 and 2004, safety and efficacy of BMP2 and 7 have been extensively investigated in randomized, blinded, and controlled trials (RCT) [42, 43].

RhBMP2 has been approved for treatment of open tibial fractures following a large RCT involving 450 patients with different types of fractures according to Gustilo-Anderson classification [44]. During 1-year follow-up period BMP2 in the higher dose (1.5 mg/mL) enhanced bone healing and reduced the number of secondary interventions when compared to patients treated with the standard of care. Major disadvantage of this study was the fact that surgeons were not blinded for patients receiving rhBMP2. In another RCT, the efficacy of rhBMP7 in tibial non-unions of 124 patients who received autologous bone graft or device containing rhBMP7 has been tested [45]. Emphasized benefit was mostly related to the lack of morbidity at the autologous bone iliac crest harvesting site and subsequently reduced intra-operative blood loss. However, rhBMP7 was less effective than the autograft bone in the tibial non-union repair.

FDA and EMA approved rhBMP2 (Infuse) for open tibial fractures and rhBMP7 as so-called humanitarian device exemption (Osigraft) for tibial non-unions [46]. In addition, rhBMP2 and 7 were used off-label in various indications including scaphoid fractures, distal radius fractures, and cervical and thoracic ALIF [47, 48, 49]. A small RCT demonstrated a successful outcome of the proximal pole scaphoid non-union by administering rhBMP7 alone or in combination with an autograft [49]. Two small sample studies with a total of 30 patients enrolled showed a complete restoration of humeral non-unions in all patients when rhBMP7 was used with an autograft [50]. RhBMP2 was slightly less effective in the same indication, and the union was accomplished in eight out of nine patients [51]. In a retrospective study, rhBMP2 and 7 failed to show advantage in the treatment of aseptic clavicle non-union. Radical resection of the non-union tissue from the clavicle was a major step in the healing process [52]. Many off-label clinical studies were performed during the last 15 years, including various skeletal sites [53].

RhBMP2 was approved by the FDA in 2002 for anterior lumbar interbody fusion (ALIF) surgeries in indications including one-level degenerative disc disease [54]. Following its approval, the use of BMP increased and had 25% share in spinal fusion procedures in US in 2006 [55]. It is important to emphasize that high proportion of these surgeries deviated from the originally FDA-approved indications, including posterior and transforaminal lumbar interbody fusion and cervical fusions. In patients treated for spinal fusion with BMP devices, it has been observed that application in unstable thoracolumbar fractures resulted in severe bone resorption, loss of reduction, and segmental collapse [56]. This effect could be explained with pronounced effect of large amount of rhBMP 2 and 7 on osteoclasts, at trabecular surfaces which form majority of vertebrae. However, the retrospective analyses revealed that the initial rhBMP-induced resorption was transient and that bone formation and repair subsequently occurred [42]. In conclusion, BMP application for spinal fusion should be restricted to approaches with safety and efficacy proven in RCTs, and those in which vertebral canal remains intact, to avoid neurological complications.

In 2007, FDA approved the use of rhBMP2 for maxillary sinus and alveolar ridge augmentation to fulfill tooth extraction sockets and intradental defects and enable installation of dental implants [57]. A randomized controlled clinical trial evaluated rhBMP2 attached to absorbable collagen sponge (mean rhBMP2 dose 1.9 mg/site) for alveolar ridge augmentation following tooth extraction, and demonstrated that extraction socket treated with rhBMP2 maintained the alveolar crestal height, while control sites without treatment showed loss in the crestal bone. Expanded RCT evaluated these findings by testing rhBMP2 at extraction sites with large bone defects. RhBMP2 achieved greater bone formation than collagen carrier alone, thus enabling formation of alveolar ridge more suitable to receive a dental implant [58]. Importantly, quality of newly formed bone after rhBMP2 treatment was the same as a regular healthy bone. Notably, when rhBMP2 was used for maxillary sinus floor augmentation, performance of newly formed bone was comparable to standard of care repair with autologous bone, with height extension ranging from 7.8 to 10.2 mm [59]. Few case series studies demonstrated the potential of both rhBMP2 and 7 in mandibular defect filling [60, 61].

However, following clinical testing for both rhBMP2 and 7 bone devices major side-effects have been reported and their therapeutic use have been recently revisited [15, 42, 43]. Local transient swelling, inflammation, and heterotopic ossification as well as early osteolysis were among serious complications following long bone implantation and spinal fusion, particularly in the cervical spine. The inflammation was pronounced in patients with distal radius fractures [62]. The average amount of rhBMP incorporated into the collagen carrier was between 3.5 and 12 mg, depending on the site and size of the fracture gap, while the entire human body normally contains only around 2 mg of BMPs. BMPs are not soluble at neutral pH and only 75 μg of the protein binds to 1 g of bovine collagen, while the rest precipitates and is locally released representing a potential source for local and systemic side effects. According to previous pharmacokinetic and bioavailability studies with commercial rhBMP devices it is expected that only 1–2% of locally administered rhBMP will be present in the patient’s circulation in the period of two weeks following implantation. It was recently suggested that the impact of potentially systemically released rhBMP2 and 7 might rather have a positive effect on the skeleton via increasing the skeletal bone volume [63].

Another serious side effect of rhBMP2 device comprises early osteolysis causing the implant to shift and result in the subsequent fracture instability, especially if the periosteum was damaged [62]. In patients with unstable thoracolumbar fractures, rhBMP7 use resulted in a substantial bone resorption, loss of reduction, and segmental collapse [64]. Upon retrospective analyses of several clinical studies, it was suggested that the observed initial bone resorption was of a transient nature and that bone formation subsequently occurred [42, 43]. This was initially overlooked due to insufficient understanding of the BMPs mechanism of action on endosteal surfaces [15].

RhBMP2 faces major drawbacks since current knowledge on bone physiology does not support its current dosing and administration using animal-derived carrier. New solutions for bone healing are therefore needed, taking into account the complexity of BMP signaling and different cellular and tissue effects [65, 66]. Tissues surrounding the injury like periosteum, endosteum, bone marrow, vascular tissue, and muscles provide progenitor cells that initiate formation of bone callus and subsequently new bone by BMPs.

BMP6 as novel therapy for bone repair

A novel rhBMP6 containing osteogenic device (osteoinductive autologous bone graft substitute, ABGS) aimed to accelerate bone regeneration was developed and is currently being tested in clinical trials [66]. It comprises of a biologically compatible autologous carrier made from the patient’s peripheral blood (autologous blood coagulum, ABC) and of rhBMP6 as an active ingredient. Such formulation circumvents the use of animal-derived materials, significantly limits inflammatory processes common in commercial bone devices and renders the carrier flexible, malleable, and injectable ensuring the ease of use.

BMP6 and BMP7 are paralogs with 87% similarity in the amino acid sequence. However, at position 60 of the mature BMP domain BMP6 contains lysine instead of aspartic acid (BMP7) or prolin (BMP2). This lysine allows for a reversible binding of BMP6 to Noggin, major BMP antagonist in tissues, so unlike BMP7 or BMP2, BMP6 may dissociate from Noggin and escape from Noggin inhibition [67]. This explains why BMP6 is more potent in promoting osteoblast differentiation in vitro and inducing bone regeneration in vivo when compared with its closely related BMP7 paralog.

ABGS successfully re-bridges critical size defects in animal models as well as enables physiological retention of rhBMP6 in the carrier upon binding to its extracellular matrix molecules and to cell membrane receptors constituting the ABC [3, 16]. This is supported by negligible absolute bioavailability following local implantation in animal models. Overall, non-clinical safety evaluation demonstrates a high safety margin for the use of ABGS in human bone defect indications. The ongoing clinical trials will provide detailed insights into the safety, tolerability, pharmacokinetics, and bone healing effects in humans and potentially provide novel and safe therapeutic options for bone repair.


Funding information

The research leading to these results has received funding from the Horizon 2020 research and innovation program under GA No. 779340 (OSTEOproSPINE) and the Scientific Center of Excellence for Reproductive and Regenerative Medicine (project “Reproductive and regenerative medicine - exploration of new platforms and potentials”, GA KK01. funded by the EU through the ERDF).

Compliance with ethical standards

Conflict of interest

IDC, LK, and Marko Pecina declare no conflict of interest. Mihaela Peric is employed by School of Medicine, University of Zagreb and is actively involved in OSTEOproSPINE program and clinical testing in patients with posterolateral spinal fusion. LG is employed by School of Medicine, University of Zagreb and actively leads the development of the final Osteogrow drug product in patients with distal radius fracture, high tibial osteotomy, and lumbar back pain. SV is employed by School of Medicine, University of Zagreb and is founder of Genera Research, a Croatian biotechnology company conducting clinical trials with Osteogrow.


  1. 1.
    Svedbom A, Hernlund E, Ivergard M, Compston J, Cooper C, Stenmark J et al (2013) Osteoporosis in the European Union: a compendium of country-specific reports. Arc Osteoporos 8:137. CrossRefGoogle Scholar
  2. 2.
    Cauley JA (2017) Osteoporosis: fracture epidemiology update 2016. Curr Opin Rheumatol 29:150–1562. CrossRefPubMedGoogle Scholar
  3. 3.
    Dumic-Cule I, Pecina M, Jelic M, Jankolija M, Popek I, Grgurevic L et al (2015) Biological aspects of segmental bone defects management. Int Orthop 39:005–1011. CrossRefGoogle Scholar
  4. 4.
    Dimitriou R, Carr IM, West RM, Markham AF, Giannoudis PV (2011) Genetic predisposition to fracture non-union: a case control study of a preliminary single nucleotide polymorphisms analysis of the BMP pathway. BMC Musculoskelet Disord 12(44).
  5. 5.
    Petrie J, Sassoon A, Haidukewych GJ (2013) When femoral fracture fixation fails: salvage options. Bone Joint J 95-B:7–10. CrossRefPubMedGoogle Scholar
  6. 6.
    Chen Y, Guo Q, Pan X, Qin L, Zhang P (2011) Smoking and impaired bone healing: will activation of cholinergic anti-inflammatory pathway be the bridge? Int Orthop 35:1267–1270. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Flouzat-Lachaniette CH, Heyberger C, Bouthors C, Roubineau F, Chevallier N, Rouard H, Hernigou P (2016) Osteogenic progenitors in bone marrow aspirates have clinical potential for tibial non-unions healing in diabetic patients. Int Orthop 40:1375–1379. CrossRefPubMedGoogle Scholar
  8. 8.
    Hernigou P, Guissou I, Homma Y, Poignard A, Chevallier N, Rouard H, Flouzat Lachaniette CH (2015) Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes. Int Orthop 39:1639–1643. CrossRefPubMedGoogle Scholar
  9. 9.
    Vukicevic S, Stavljenic A, Pecina M (1995) Discovery and clinical applications of bone morphogenetic proteins. Eur J Clin Chem Clin Biochem 33:661–671PubMedGoogle Scholar
  10. 10.
    Vukicevic S, Sampath TK (2008) Bone morphogenetic proteins: from local to systemic therapeutics. Basel-Boston-Berlin: Birkauser Verlag AGGoogle Scholar
  11. 11.
    Grgurevic L, Christensen GL, Schulz TJ, Vukicevic S (2016) Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism. Cytokine Growth Factor Rev 27:105–118. CrossRefPubMedGoogle Scholar
  12. 12.
    Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899CrossRefGoogle Scholar
  13. 13.
    Grgurevic L, Pecina M, Vukicevic S (2017) Marshall R. Urist and the discovery of bone morphogenetic proteins. Int Orthop 41:1065–1069. CrossRefPubMedGoogle Scholar
  14. 14.
    Reddi AH, Huggins C (1972) Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc Natl Acta Sci USA 69:1601–1605CrossRefGoogle Scholar
  15. 15.
    Vukicevic S, Oppermann H, Verbanac D, Jankolija M, Popek I, Curak J et al (2014) The clinical use of bone morphogenetic proteins (BMPs) revisited: a novel BMP6 biocompatible carrier device OSTEOGROW for bone healing. Int Orthop 38:635–647. CrossRefPubMedGoogle Scholar
  16. 16.
    Vukicevic S, Sampath TK (ed) (2017) Bone morphogenetic proteins: systems biology regulators, 1st edn Springer International Publishing AG, SwitzerlandGoogle Scholar
  17. 17.
    van Baardewijk LJ, van der Ende J, Lissenberg-Thunnissen S, Romijn LM, Hawinkels LJ, Sier CF, Schipper IB (2013) Circulating bone morphogenetic protein levels and delayed fracture healing. Int Orthop 37:523–527. CrossRefPubMedGoogle Scholar
  18. 18.
    Kamiya N, Ye L, Kobayashi T, Lucas DJ, Mochida Y, Yamauchi M et al (2008) Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J Bone Miner Res 23:2007–2017. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Okamoto M, Murai J, Imai Y, Ikegami D, Kamiya N, Kato S et al (2011) Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. J Bone Miner Res 26:2511–2522. CrossRefPubMedGoogle Scholar
  20. 20.
    Okamoto M, Murai J, Yoshikawa H, Tsumaki N (2006) Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 21:1022–1033. CrossRefPubMedGoogle Scholar
  21. 21.
    Minear S, Leucht P, Miller S, Helms JA (2010) rBMP represses Wnt signaling and influences skeletal progenitor cell fate specification during bone repair. J Bone Miner Res 25:1196–1207. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kamiya N, Kobayashi T, Mochida Y, Yu PB, Yamauchi M, Kronenberg HM et al (2010) Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res 25:200–210. CrossRefPubMedGoogle Scholar
  23. 23.
    Giles EM, Godbout C, Chi W, Glick MA, Lin T, Li R, Schemitsch EH, Nauth A (2017) Subtypes of endothelial progenitor cells affect healing of segmental bone defects differently. Int Orthop 41:2337–2343. CrossRefPubMedGoogle Scholar
  24. 24.
    Bolander J, Chai YC, Geris L, Schrooten J, Lambrechts D, Roberts SJ, Luyten FP (2016) Early BMP, Wnt and Ca(2+)/PKC pathway activation predicts the bone forming capacity of periosteal cells in combination with calcium phosphates. Biomaterials 86:106–118. CrossRefPubMedGoogle Scholar
  25. 25.
    Kalfas IH (2001) Principles of bone healing. Neurosurg Focus 10:E1-. CrossRefGoogle Scholar
  26. 26.
    Reddi AH, Cunningham NS (1993) Initiation and promotion of bone differentiation by bone morphogenetic proteins. J Bone Miner Res 8(Suppl 2):S499–S502. CrossRefPubMedGoogle Scholar
  27. 27.
    Dimitriou R, Tsiridis E, Giannoudis PV (2005) Current concepts of molecular aspects of bone healing. Injury 36:1392–1404. CrossRefPubMedGoogle Scholar
  28. 28.
    Cho TJ, Gerstenfeld LC, Einhorn TA (2002) Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 17:513–520. CrossRefPubMedGoogle Scholar
  29. 29.
    Edgar CM, Chakravarthy V, Barnes G, Kakar S, Gerstenfeld LC, Einhorn TA (2007) Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells. Bone 40:1389–1398. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cheng H, Jiang W, Phillips FM, Haydon RC, Peng Y, Zhou L et al (2003) Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am 85-A:1544–1552. CrossRefPubMedGoogle Scholar
  31. 31.
    Asahina I, Sampath TK, Nishimura I, Hauschka PV (1993) Human osteogenic protein-1 induces both chondroblastic and osteoblastic differentiation of osteoprogenitor cells derived from newborn rat calvaria. J Cell Biol 123:921–933. CrossRefPubMedGoogle Scholar
  32. 32.
    Onishi T, Ishidou Y, Nagamine T, Yone K, Imamura T, Kato M et al (1998) Distinct and overlapping patterns of localization of bone morphogenetic protein (BMP) family members and a BMP type II receptor during fracture healing in rats. Bone 22:605–612. CrossRefPubMedGoogle Scholar
  33. 33.
    Dejaeger M, Böhm AM, Dirckx N, Devriese J, Nefyodova E, Cardoen R, St-Arnaud R, Tournoy J, Luyten FP, Maes C (2017) Integrin-linked kinase regulates bone formation by controlling cytoskeletal organization and modulating BMP and Wnt signaling in Osteoprogenitors. J Bone Miner Res 32:2087–2102. CrossRefPubMedGoogle Scholar
  34. 34.
    Ali IH, Brazil DP (2014) Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. Br J Pharmacol 171:3620–3632. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kloen P, Di PM, Borens O, Richmond J, Perino G, Helfet DL, Goumans MJ (2003) BMP signaling components are expressed in human fracture callus. Bone 33:362–371. CrossRefPubMedGoogle Scholar
  36. 36.
    Kwong FN, Hoyland JA, Evans CH, Freemont AJ (2009) Regional and cellular localisation of BMPs and their inhibitors’ expression in human fractures. Int Orthop 33:281–288. CrossRefPubMedGoogle Scholar
  37. 37.
    Wan DC, Pomerantz JH, Brunet LJ, Kim JB, Chou YF, Wu BM et al (2007) Noggin suppression enhances in vitro osteogenesis and accelerates in vivo bone formation. J Biol Chem 282:26450–26459. CrossRefPubMedGoogle Scholar
  38. 38.
    Chhabra A, Zijerdi D, Zhang J, Kline A, Balian G, Hurwitz S (2005) BMP-14 deficiency inhibits long bone fracture healing: a biochemical, histologic, and radiographic assessment. J Orthop Trauma 19:629–634. CrossRefPubMedGoogle Scholar
  39. 39.
    Niikura T, Hak DJ, Reddi AH (2006) Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures. J Orthop Res 24:1463–1471. CrossRefPubMedGoogle Scholar
  40. 40.
    Kwong FN, Hoyland JA, Freemont AJ, Evans CH (2009) Altered relative expression of BMPs and BMP inhibitors in cartilaginous areas of human fractures progressing towards nonunion. J Orthop Res 27:752–757. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kloen P, Lauzier D, Hamdy RC (2012) Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions. Bone 51:59–68. CrossRefPubMedGoogle Scholar
  42. 42.
    Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R et al (2013) Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med 158:890–902. CrossRefPubMedGoogle Scholar
  43. 43.
    Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA et al (2013) Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med 158:877–889. CrossRefPubMedGoogle Scholar
  44. 44.
    Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R et al (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 84-A:2123–2134. CrossRefPubMedGoogle Scholar
  45. 45.
    Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF et al (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A(Suppl 1):S151–S158. CrossRefGoogle Scholar
  46. 46.
    Giannoudis PV, Kanakaris NK (2017) BMPs in orthopaedic medicine: promises and challenges. In: Vukicevic S, Sampath TK (eds) Bone morphogenetic proteins: systems biology regulators, 1st edn. Springer International Publishing AG, Switzerland, pp 187–214CrossRefGoogle Scholar
  47. 47.
    Pecina M, Giltaij LR, Vukicevic S (2001) Orthopaedic applications of osteogenic protein-1 (BMP-7). Int Orthop 25:203–208. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pecina M, Haspl M, Jelic M, Vukicevic S (2003) Repair of a resistant tibial non-union with a recombinant bone morphogenetic protein-7 (rhBMP-7). Int Orthop 27:320–321. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Bilic R, Simic P, Jelic M, Stern-Padovan R, Dodig D, van Meerdervoort HP et al (2006) Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis. Int Orthop 30:128–134. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Giannoudis PV, Kanakaris NK, Dimitriou R, Gill I, Kolimarala V, Montgomery RJ (2009) The synergistic effect of autograft and BMP-7 in the treatment of atrophic nonunions. Clin Orthop Relat Res 467:3239–3248. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Crawford CH III, Seligson D (2009) Atrophic nonunion of humeral diaphysis treated with locking plate and recombinant bone morphogenetic protein: nine cases. Am J Orthop (Belle Mead NJ) 38:567–570Google Scholar
  52. 52.
    von Rüden C, Morgenstern M, Friederichs J, Augat P, Hackl S, Woltmann A, Bühren V, Hierholzer C (2016) Comparative study suggests that human bone morphogenetic proteins have no influence on the outcome of operative treatment of aseptic clavicle non-unions. Int Orthop 40:2339–2345. CrossRefGoogle Scholar
  53. 53.
    Courvoisier A, Sailhan F, Laffenêtre O, Obert L, French Study Group of BMP in Orthopedic Surgery (2014) Bone morphogenetic protein and orthopaedic surgery: can we legitimate its off-label use? Int Orthop 38:2601–2605. CrossRefPubMedGoogle Scholar
  54. 54.
    Faundez A, Tournier C, Garcia M, Aunoble S, Le Huec JC (2016) Bone morphogenetic protein use in spine surgery-complications and outcomes: a systematic review. Int Orthop 40:1309–1319. CrossRefPubMedGoogle Scholar
  55. 55.
    Cahill KS, Chi JH, Day A, Claus EB (2009) Prevalence, complications, and hospital charges associated with use of bone-morphogenetic proteins in spinal fusion procedures. JAMA 302:58–66. CrossRefPubMedGoogle Scholar
  56. 56.
    Laursen M, Høy K, Hansen ES, Gelineck J, Christensen FB, Bünger CE (1999) Recombinant bone morphogenetic protein-7 as an intracorporal bone growth stimulator in unstable thoracolumbar burst fractures in humans: preliminary results. Eur Spine J 8:485–490CrossRefGoogle Scholar
  57. 57.
    Wikesjö UME, Susin C (2017) BMPs in dental medicine: promises and challenges. In: Vukicevic S, Sampath TK (eds) Bone morphogenetic proteins: systems biology regulators, 1st edn. Springer International Publishing AG, Switzerland, pp 249–270CrossRefGoogle Scholar
  58. 58.
    Fiorellini JP, Howell TH, Cochran D, Malmquist J, Lilly LC, Spagnoli D et al (2005) Randomized study evaluating recombinant human bone morphogenetic protein-2 for extraction socket augmentation. J Periodontol 76:605–613. CrossRefPubMedGoogle Scholar
  59. 59.
    Triplett RG, Nevins M, Marx RE, Spagnoli DB, Oates TW, Moy PK et al (2009) Pivotal, randomized, parallel evaluation of recombinant human bone morphogenetic protein-2/absorbable collagen sponge and autogenous bone graft for maxillary sinus floor augmentation. J Oral Maxillofac Surg 67:1947–1960. CrossRefPubMedGoogle Scholar
  60. 60.
    Desai SC, Sclaroff A, Nussenbaum B (2013) Use of recombinant human bone morphogenetic protein 2 for mandible reconstruction. JAMA Facial Plast Surg 15:204–209. CrossRefPubMedGoogle Scholar
  61. 61.
    Clokie CM, Sandor GK (2008) Reconstruction of 10 major mandibular defects using bioimplants containing BMP-7. J Can Dent Assoc 74:67–72PubMedGoogle Scholar
  62. 62.
    Ekrol I, Hajducka C, Court-Brown C, McQueen MM (2008) A comparison of rhBMP-7 (OP-1) and autogenous graft for metaphyseal defects after osteotomy of the distal radius. Injury 39(Suppl 2):S73–S82. CrossRefPubMedGoogle Scholar
  63. 63.
    Dumic-Cule I, Brkljacic J, Rogic D, Bordukalo-Niksic T, Tikvica Luetic A, Draca N et al (2014) Systemically available bone morphogenetic protein two and seven affect bone metabolism. Int Orthop 38:1979–1985. CrossRefPubMedGoogle Scholar
  64. 64.
    Pradhan BB, Bae HW, Dawson EG, Patel VV, Delamarter RB (2006) Graft resorption with the use of bone morphogenetic protein: lessons from anterior lumbar interbody fusion using femoral ring allografts and recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976) 31:E277–E284. CrossRefGoogle Scholar
  65. 65.
    Krishnakumar GS, Roffi A, Reale D, Kon E, Filardo G (2017) Clinical application of bone morphogenetic proteins for bone healing: a systematic review. Int Orthop 41:1073–1083. CrossRefPubMedGoogle Scholar
  66. 66.
    Vukicevic S, Grgurevic L, Pecina M (2017) Clinical need for bone morphogenetic proteins. Int Orthop 41:2415–2416. CrossRefPubMedGoogle Scholar
  67. 67.
    Song K, Krause C, Shi S, Patterson M, Suto R, Grgurevic L et al (2010) Identification of a key residue mediating bone morphogenetic protein (BMP)-6 resistance to noggin inhibition allows for engineered BMPs with superior agonist activity. J Biol Chem 285:12169–12180. CrossRefPubMedPubMedCentralGoogle Scholar

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© The Author(s) 2018

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Ivo Dumic-Cule
    • 1
  • Mihaela Peric
    • 2
  • Lucija Kucko
    • 1
  • Lovorka Grgurevic
    • 1
  • Marko Pecina
    • 3
  • Slobodan Vukicevic
    • 1
    Email author
  1. 1.Center for Translational and Clinical Research, Laboratory for Mineralized TissuesUniversity of Zagreb School of MedicineZagrebCroatia
  2. 2.Center for Translational and Clinical Research, Department for Intercellular communicationUniversity of Zagreb School of MedicineZagrebCroatia
  3. 3.Department of OrthopaedicsUniversity of Zagreb School of MedicineZagrebCroatia

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