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A current outlook on bone metabolism and fracture healing
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Editor’s note: In the first part of an article from the FORTE organization, members of the Orthopaedics and Traumatology Department at Hacettepe University, in Ankara, Turkey, discuss the role bones play in the body and how cells support skeletal remodeling. Look for the second part of the article, about principles of fracture healing and bone metabolism, as well as the full list of references, in the January 2016 issue of Orthopaedics Today Europe.
Fracture healing consists of a complex healing cascade in which bone undergoes one of the unique regeneration processes in the human body. Before the last 2 decades, bone was thought to have an ordinary metabolism and our knowledge about fracture healing was limited. As new molecules and pathways of fracture healing were found, our understanding of the biology of bone changed significantly. The bone healing process can be described as a repetition of bone embryological development and a living example of the tissue regeneration process. If bone fails to regenerate and is unable to maintain the complex mechanism involved the healing process, nonunions and pseudoarthrosis can develop, as well as undesirable anatomical positioning of the bone. In this review, we discuss the cellular biology of the bone and the fracture healing process to update our knowledge about fractures.
Bones form template for the body
When we are born, we have more than 270 bones and, due to fusion at the centers of ossification, we have 206 bones for the rest of our lives. Contrary to what is believed, bones are non-static tissues, which change due to biomechanical forces that renew the old parts of the bone and rebuild bone tissue through a biomechanically stronger bond that is possible through the remodeling process. Thanks to this remodeling process, the human skeleton performs a nonstop renovation. Our skeleton is multifunctional; it provides a strong template for the body, makes locomotion possible, sustains mineral homeostasis via the hormones and mineral depots, and harbors hematopoiesis in bone marrow.
Compared with other tissues in our body in which metabolic turnover is faster than bone, bones are thought to be more like a desert in our body. This may be true just for the sake of comparison, but recent studies have evaluated how bones can manage unique regeneration processes and complex metabolic events. An examination of the histology of bone reveals clues about the complex metabolism of bone.
Cortical or trabecular bone
Histologically, bones are classified as cortical or trabecular. Cortical bone, which is made of osteons and Haversian canals, is the dense, outer part of a bone. The Haversian canals have a tree-shaped structural network within the cortical bone and are cylindrical. Cortical bone is a huge tissue with more than 20 million cortical osteons and a Haversian system of 3.5 m2 in size. Trabecular bone has no Haversian system, but has its own characteristic osteons that follow its trabecular shape. Collagen fibrils are formed in a lamellar pattern in cortical and trabecular bone and, as such, give bones strength.
Bone contains four types of cells: osteoblasts, bone lining cells, osteocytes and osteoclasts, and each type of cell has a relationship with the other types. They respond to environmental changes outside the bone via cytokines and growth factors. To date, the function of bone lining cells has not been well-identified. During the remodeling process, all these cells together form a basic multicellular unit (BMU), which is essential to the remodeling processes. Bone is able to adapt to mechanical forces with remodeling. In this process, because of biomechanical stimulation, multiple local and systemic hormones and cytokines are key factors that contribute to the balance between bone resorption and formation.
Osteoblasts are cuboidal cells that comprise 4% to 6% of all bone cells. Their main function is to produce new bone tissue called the osteoid. Osteoblasts are derived from mesenchymal stem cells (MSC) through interaction with specific genes. The Wingless (Wnt) receptors and bone morphogenetic proteins (BMP) are the main genes that lead the process that transforms MSCs into osteoblast precursor cells. The expression of the runt-related transcription factor 2 (Runx2) gene indicates the osteoblast differentiation after the interaction of Wnt and BMP. Thus, Runx2 is the main gene of osteoblast differentiation and it upregulates osteoblast-related genes. After the differentiation is completed, alkaline phosphatase activity maintains its role in the proliferation process. Further protein expression, such as those of osteocalcin, type 1 collagen, bone sialoprotein and morphological changes, turn pre-osteoblasts into mature osteoblasts. Recent studies showed other proteins, such as growth factors, microRNAs and connexin 43, should be considered important influencers in the differentiation of osteoblasts. Their role in fracture healing processes also is being investigated.
Bone lining cells are thin-shaped cells that originate from osteoblasts on the bone surface. They perform a process that creates finger-like extensions into canaliculi and gap junctions. It is estimated they interact with bone’s inner parts and play a potent role in bone metabolism. Their complete action, however, is not well understood. Some studies have shown they are capable of transforming into osteoblasts when needed and play an important part in the BMU. It is also reported that bone lining cells digest collagen left by osteoclasts.
Plentiful osteocytes
Osteocytes comprise nearly 90% of total bone cells and have a long life. For decades, they were believed to be passive living cells in the bone matrix until new research and technology led to a better understanding of their capabilities. Osteocytes are located in a lacunae and have extensive dendrite-like processes that create a network with other lacunae. This network functions as a transducer of mechanical signals into biologic activity. Connexin 43 is the main molecule that enables mechanical signals to interact between the gap junctions. There are two main theories about how bone remodeling occurs — the mechanotransduction and piezoelectric theories. The mechanotransduction theory is based on the existence of a connection between bone cells and how the cells respond to biomechanical forces, whereas the piezoelectric theory explains the responses to stretching and bending forces with the transformation due to electrical forces in bone cells.
Osteoclasts are multinucleated cells present in bone tissue that stem from a monocyte-macrophage system. There are two main cytokines that stimulate osteoclast differentiation. Receptor activator nuclear factor-KB ligand (RANKL), which is produced by osteoblasts and MSCs, belongs to tumor necrosis factor (TNF)-receptor superfamily. Macrophage colony-stimulating factor (M-CSF) is found in bone marrow and has the power to force stem cells to undergo osteoclastogenesis. Gene expression and activation of transcription factors are mainly promoted by these two factors.
More recently, osteoclasts were recognized more as secretory immune cells due to their interaction with other immune cells in different rheumatologic diseases and much new research has been done to reinforce this relationship.
Osteoprotegerin molecule involved in bone metabolism
Osteoprotegerin (OPG), which combines the Latin words osteo (bone) and protegere (to protect), is a molecule involved in bone metabolism that was discovered in the 1990s. Animal studies have helped further the understanding of the mechanism of the RANKL/RANK/OPG signaling system. Nuclear factor kappa-light-chain-enhancer of activated B cells (NK-KB) is activated through differentiation of osteoclasts and is a transcription factor for specific proteins in cell metabolism. OPG is a decoy receptor for RANKL and prevents the activation of NF-KB and therefore prevents osteoclastogenesis. It is secreted by osteoblasts, stromal cells and fibroblasts.
Denosumab is a monoclonal antibody that acts as a RANKL inhibitor and mimics the effects of OPG. Denosumab is approved by the U.S. Food and Drug Administration for the treatment of postmenopausal osteoporosis. Boron and colleagues showed single mononucleotide polymorphisms can cause variations between the affinity of OPG molecules individually and help with predicting osteoporosis risk for patients. Other studies showed OPG is found systemically in the body, especially in patients with metabolic disorders such as diabetes and coronary artery disease. However, it is not clear whether high levels of OPG in metabolic disorders is a cause or effect of these diseases. There is also some evidence high OPG levels can cause calcification of atheromatous plaque and endothelial proliferation.
This research widens the perspective on the role OPG plays in our body. It is thought the RANKL/OPG pathway has either an inflammatory, endocrine and pro-oncogenic effect on different organ systems.
- For more information:
- Mahmut Nedim Doral, MD, can be reached at email: mndoral@gmail.com.
- Gazi Huri, MD, can be reached at email: gazihuri@yahoo.com.
- Mehmet Kaymakoglu, MD, can be reached at email: kaymakoglumehmet@gmail.com.
- Egemen Turhan, MD, can be reached at email: dregementurhan@yahoo.com.
- Altug Yücekul, MD, can be reached at email: ayucekul@hotmail.com.
- Doral, Huri, Kaymakoglu, Turhan and Yücekul are at the Orthopaedics and Traumatology Department, Hacettepe University, 06230 Ankara, Turkey.
Disclosures: Doral, Huri, Kaymakoglu, Turhan and Yücekul report no relevant financial disclosures.