Introduction
Bone stands out as one of the exceptional tissues within the adult human body, possessing the remarkable capacity to naturally mend, rejuvenate, and fully reinstate its functionality following fractures. In the European Union, a staggering 3.5 million bone fractures were officially documented in the year 2010. Projections indicate that by the year 2050, over 50 million individuals, both men and women, will face the potential risk of bone fractures stemming from conditions like osteopenia and osteoporosis.
What Are the Key Stages in the Bone Healing Process?
The bone healing process serves as a model for tissue engineering, involving signals, cells, and substrates. It comprises three stages: early inflammation and cell recruitment (callus formation), cell differentiation and new bone formation (fracture repair), and late bone remodeling (restoration). While most fractures heal naturally, complicated or open fractures can lead to indirect healing due to incomplete stability, impacting bone formation.
Intramembranous ossification (the process by which bones are formed directly from sheets or layers of connective tissue) occurs near the injury site, while endochondral ossification (the process by which bones grow and develop from cartilage) develops centrally after callus formation. Improper healing can result in severe consequences, such as disfigurement, loss of function, or limb loss. To promote successful bone union, factors like blood supply, a sterile environment, mechanical stability, and proper soft tissue management are crucial.
Genetic factors can contribute to non-union fractures, with defective BMP signaling linked to non-union. Around ten percent of cases experience slow healing (mal-union) or no healing (non-union), necessitating additional medical interventions, particularly in smokers and steroid users. Risk factors for impaired bone healing include old age, smoking, osteoporosis, diabetes, and NSAID (non-steroidal anti-inflammatory drugs) use.
What Is the Role of Bone Morphogenetic Proteins (BMPs) In Skeletal Development and Fracture Healing?
Bone morphogenetic proteins (BMPs) are crucial for skeletal development and adult fracture healing, mimicking embryonic bone formation processes. Over 30 types of BMPs have been identified, with some having functions beyond bone. BMPs are divided into groups based on amino acid sequences. In 1965, Marshall Urist discovered that demineralized bone can induce new bone growth at ectopic sites. This process involves mesenchymal cell recruitment, differentiation, and vascular invasion. BMP-induced ectopic bone formation relies on progenitor cells near blood vessels and connective tissues without the need for osteoclasts. The response to BMPs depends on the local microenvironment and cell types present. Skeletal progenitor cells for bone healing come from various tissue compartments. BMPs are more effective when pluripotential cells are abundant. However, bone remodeling requires coupling between osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells), which depends on local cytokine signaling (a messaging system in the body where cells release special proteins called cytokines to communicate with other cells) and hormones. Currently, BMP effects are studied after local implantation, and there is limited data on the relationship between circulating BMP levels and fracture healing.
What Are the Recent Findings Regarding the Effects of Bone Morphogenetic Proteins (BMPs) On Bone Formation?
Recent studies challenge the conventional belief that bone morphogenetic proteins (BMPs) primarily induce bone formation at endosteal bone sites. In mouse models, inhibiting BMPR-IA receptor signaling in osteoblasts led to increased bone volume, while deleting the same receptor in differentiated osteoclasts resulted in increased osteoblastic bone formation. BMP4 overexpression in osteoblasts causes bone loss, and intramedullary BMP2 suppresses osteogenesis by downregulating key factors. Additionally, BMP signaling inhibited Wnt signaling in osteoblasts. These findings suggest that osteogenic BMPs can lead to net bone loss due to their stronger effect on osteoclasts than osteoblasts.
In contrast to in vitro evidence, BMP2 and BMP7, when applied at orthotopic bone sites, can result in bone loss. However, when delivered at ectopic sites or near the periosteum or muscle, they promote bone formation and healing by expanding new bone formation from uncoupled to coupled bone surfaces, eventually incorporating into an endogenous coupled bone microenvironment. Calcium phosphate-based biomaterials further influence the quality of newly formed bone by activating BMP, Wnt, and PKC signaling pathways, discriminating between bone-forming and non-bone-forming constructs.
What Are the Key Stages and Roles of Bone Morphogenetic Proteins (BMPs) In the Process of Fracture Healing and Bone Formation?
The process of fracture healing involves a series of stages, including an early inflammatory phase, a repair phase, and a late remodeling phase. Most fractures undergo a combination of intramembranous and endochondral ossification, leading to callus formation. Bone Morphogenetic Proteins (BMPs) play a significant role in this process. BMPs like BMP2, BMP4, and BMP7 are highly upregulated in the early phase, promoting intramembranous ossification directly under the periosteum. BMP signaling facilitates the differentiation of mesenchymal stem cells (MSCs) into chondroblasts and osteoblasts, contributing to soft callus formation.
During the osteogenic stage of bone repair, BMP3, BMP4, BMP7, and BMP8 are expressed, coinciding with the resorption of calcified cartilage, recruitment of osteoblasts, and bone formation. BMP2, BMP6, and BMP9 are particularly potent inducers of MSC differentiation into osteoblasts. Proper angiogenesis in the late phase enables the replacement of cartilage tissue with woven bone, which subsequently undergoes remodeling to restore normal bone function.
The interaction between osteoblasts and osteoclasts occurs at specific sites known as bone metabolic units (BMUs). BMP signaling affects osteoblasts differently depending on their maturation stage, enhancing their early phase but having minimal influence on mature osteoblasts. BMP2, BMP4, and BMP7 have been detected in osteoclast-like cells during the formation of newly trabecular bone.
BMPs, particularly BMPs like BMP2, BMP4, and BMP7, play a central role in providing chemotactic signals for osteoprogenitors, influencing cytoskeletal organization, and adjusting BMP signaling in these cells. Mice lacking functional integrin-linked kinase in osterix-expressing cells have shown reduced trabecular bone mass, highlighting the importance of this kinase in bone formation.
What Is BMP-Based Therapy for Fracture Healing?
BMP-based therapy for fracture healing has been extensively studied following FDA (the United States Food and Drug Administration) approval of BMP2 and BMP7. BMP2 showed promise in open tibial fractures, enhancing bone healing and reducing secondary interventions. However, BMP7 was less effective in tibial non-unions compared to autografts. These BMPs were also used off-label in various indications, including spinal fusions and dental procedures.
In spinal fusion, BMP application was associated with complications, including bone resorption and segmental collapse, particularly in unstable fractures. These issues have prompted the need for restricting BMP use to proven approaches.
In dental procedures, BMP2 demonstrated benefits in maintaining alveolar crest height and enabling dental implant placement. However, clinical testing revealed serious side effects, such as swelling, inflammation, and early osteolysis, leading to a reevaluation of their therapeutic use.
Newer BMPs like BMP6, with improved properties and formulations, are being developed to accelerate bone regeneration while minimizing complications. These novel approaches aim to harness the potential of BMPs more effectively in fracture healing and bone repair.
What Is BMP6 as a Novel Therapy for Bone Repair?
A novel osteogenic device containing rhBMP6 is under clinical trials for bone regeneration. This device uses an autologous carrier from the patient's blood and circumvents inflammatory issues, offering flexibility and ease of use. Unlike BMP7 and BMP2, BMP6's structure allows it to bind reversibly to Noggin, a major antagonist, enhancing its potency in promoting osteoblast differentiation and bone regeneration. The device successfully repairs critical defects in animal models by retaining rhBMP6, binding to the extracellular matrix and cell receptors. Non-clinical evaluations show high safety, and ongoing trials will reveal more about safety, effectiveness, and potential for novel bone repair treatments.
Conclusion
In conclusion, Bone Morphogenetic Proteins (BMPs) are pivotal players in the intricate process of fracture healing. They regulate inflammation, stimulate stem cell differentiation, promote soft and hard callus formation, and influence the interaction between bone-forming osteoblasts and bone-resorbing osteoclasts. This multifaceted role of BMPs underscores their significance in restoring damaged bone tissue, making them a focus of therapeutic strategies for enhancing fracture healing and bone regeneration.
