Bone Osteoblasts: Drivers of Bone Development and Repair

Bone Osteoblasts: Drivers of Bone Development and Repair

Osteoblasts are bone cells that synthesize the extracellular matrix (ECM) of bone and coordinate the bone modelling with other cells. The process is vital for bone development and fracture repair. Any imbalance in the process can cause severe disorders like osteoporosis. Several therapeutic options are currently under investigation. However, understanding osteoblast differentiation is crucial to develop an effective treatment modality. This blog provides a brief description of the process.

Bone Osteoblasts: The Bone Builders

Osteoblasts exhibit a cuboidal morphology and are present at the bone surface. They contain abundant basophilic cytoplasm and a high quantity of rough endoplasmic reticulum, along with 1-3 nucleoli in the nucleus. These cells secrete matrix proteins such as collagen, osteocalcin, alkaline phosphatase, osteopontin, sialoprotein, osteoprotegerin (OPG) and osteonectin. However, osteoblasts are not terminally differentiated cells. As the matrix calcifies, osteoblasts are buried in it and differentiate further into osteocytes. The osteoblasts that do not differentiate undergo apoptosis.

Differentiation of Bone Osteoblasts: The Key Process

Mesenchymal stem cells in bone marrow differentiate into preosteoblasts, which are then maturated into osteoblasts. This complex process occurs in three phases-proliferation, maturation, and mineralization. Each phase expresses signature markers. The MSCs multiply in the proliferative phase for 3-4 days, displaying expression of collagen, osteopontin, fibronectin, and TGFβ. Thereafter, cells exit the cell cycle and deposit the collagen and non-collagenous matrix proteins for maturation of ECM while expressing collagen and osteoblastogenesis marker-alkaline phosphatase (ALP). In the last phase, osteoblasts secrete hydroxyapatite, resulting in mineralization and the expression of osteocalcin. Several factors, such as bone morphogenic protein (BMP), fibroblast growth factor (FGF), insulin-like growth factor (IGF), parathyroid hormone (PTH), and Wingless (Wnt) proteins, regulate this process.

Driving Differentiation: The Underlying Pathways

Genes like Sox2, Msx2, and hedgehog are responsible for the commitment of MSCs towards osteoblast lineage. Wnt protein binds to its receptor and activates a canonical signalling pathway that suppresses the destruction of β-catenin, ultimately leading to the expression of osterix, RUNX2, and Distal-less homeobox 5 (Dlf), which promote the synthesis of protein required for osteoblast formation. Osterix (SP7) mediates the commitment of MSCs to osteoblast lineage. Core binding factor alpha-1 (Cbfa-1) or runt-related genes 2 (RUNX2) is the master transcriptional regulator of differentiation to osteoblasts. Activation of RUNX2 initiates the differentiation process. 

BMP interacts with type I and II serine/threonine kinase receptors and causes the activation of Smad proteins that interact with Runx2 to stimulate the expression gene required for osteoblast formation.  

Applications of Bone Osteoblasts

Mechanisms: Scientists are investigating these cells to uncover the pathophysiology of bone-related diseases such as osteoporosis, osteoarthritis, and bone metastasis. Additionally, the pathways in osteoblasts regulating the remodelling during injury are also under exploration. The delicate balance between osteoblasts and osteoclasts maintains the homeostasis of bone. Studies have suggested that abnormal expression of receptor activators for nuclear factor κB (RANKL) and OPG cause osteoblast dysfunction.

Culture Models: The in vitro culture model facilitates experimentation in an effortless manner. The osteoblast culture models include cell lines and primary cells. For example, the MG-63 cell line belongs to human osteosarcoma, the hFOB 1.19 cell line is created by transfection of human fetal osteoblast and the murine cell line, MC3T3-E1. However, cell lines do not provide physiologically relevant data. Therefore, the lab employs primary osteoblasts from the tissue or from the in vitro differentiation of MSCs.

Scaffolds: It has been discovered that scaffolds are useful platforms for bone regeneration. A number of factors, including geometry, topology, hydrophilicity, stiffness, and surface charge affect the performance of scaffolds. However, the two most important components for bone healing are osteoconductivity and osteoinductivity. They permit osteoblasts to proliferate and differentiate, respectively. The pore size determines the mass transfer across scaffolds, whereas surface area enables cell growth. Many biomaterials like polylactic acid, polyglycolic acid, polycaprolactone, etc., have been evaluated for scaffold formation.

Gene Therapy: Cell therapy with primary osteoblasts can potentially restore the damage. Gene therapy can enhance and prolong these effects, especially for genetic disorders. It alters the genes responsible for bone regeneration like PTH, RUNX2, Osterix, VEGF, BMP, etc. 

Co-culture:  To understand the pathways behind remodelling after injury, the coordination of osteoblast with osteoclasts and the role of endothelial cells need to be delineated. The culture of these cells can provide insights into the cell-cell interaction and the microenvironment formed by them.

Future Perspectives

Osteoblasts have diverse applications in tissue engineering and delineating repair pathways. Scientists are attempting to create implantable scaffolds. The hurdles in osteoblast-based therapy arise from the in vitro culture of osteoblasts, optimizing the scaffold, and integrating angiogenic factors in bioengineered tissue. Additionally, cost and scaling up have also posed a challenge. However, with the extensive ongoing research on osteoblast differentiation and their cellular interactions in bone modelling, the future might witness the conception of an effective therapy for the one-related disorder. Kosheeka provides bone osteoblasts to accelerate your research on osteoblasts and bring you closer to that future.