Insights into the Cellular and Molecular Mechanisms That Govern the Fracture-Healing Process: A Narrative Review

Abstract

Fracture-healing is a complex multi-stage process that usually progresses flawlessly, resulting in restoration of bone architecture and function. Regrettably, however, a considerable number of fractures fail to heal, resulting in delayed unions or non-unions. This may significantly impact several aspects of a patient's life. Not surprisingly, in the past few years, a substantial amount of research and number of clinical studies have been designed, aiming at shedding light into the cellular and molecular mechanisms that regulate fracture-healing. Herein, we present the current knowledge on the pathobiology of the fracture-healing process. In addition, the role of skeletal cells and the impact of marrow adipose tissue on bone repair is discussed. Unveiling the pathogenetic mechanisms that govern the fracture-healing process may lead to the development of novel, smarter, and more effective therapeutic strategies for the treatment of fractures, especially of those with large bone defects.

Keywords: bone marrow adiposity; bone ossification; bone remodeling; fracture-healing; skeletal stem cells.

Figure 1

Schematic presentation of the cellular and molecular events that characterize bone remodeling. Briefly, microfractures that take place during every day normal activities activate the mechanoresponsive osteocytes, which in turn, through their cytoplasmic projections, send signals to bone lining cells that are retracted, leaving free space on bone surfaces for osteoclasts. Pro-osteoclasts are attracted to this denuded area and differentiate to mature and active multinucleate osteoclast that start bone resorption. During bone degradation osteoblast attracting molecules, such TGF beta are released, leading to diffraction and activation of osteoblasts that reach the resorbed area and start to synthesize new bone. The circle is repeated continuously, according to the applied mechanically forces. Disturbances in the well-balanced circle of bone remodeling result in bone pathologies, including inadequate fracture-healing.

Figure 2

Histologic section of fracture site during the early, fibrous callus formation phase. The area between the fractured host bone is occupied by newly formed blood vessels in a background of loose connective tissue and organized hematoma. These are the histopathological hallmarks of the fibrovascular phase of fracture-healing (original magnification 5×).

Figure 3

Graphical presentation of the cytokines and molecular signals that participate in the early steps of the anabolic phase of fracture hearing (see text for details).

Figure 4

Histological section that depicts the cellular and molecular features of fibrocartilaginous callus which is formed during the anabolic phase of fracture-healing. Hypoxic conditions and mechanical stimulation determine whether SSC will follow the osteoblastic or the chondroblastic line of differentiation, giving genesis to bone and cartilage respectively, two cardinal elements of this phase of the fracture repair process. At the end of the anabolic phase the fractured bone parts are stabilized by hard (boney) callus (original magnification 5×).

Figure 5

This graph illustrates the cells, signaling pathways and transcription factors that regulate the late stage of the anabolic phase of fracture-healing that leads to the synthesis of fibrocartilage and eventually bone, via a process the recapitulates endochondral ossification (see text for details).

Figure 6

The catabolic phase of fracture-healing is characterized by reshaping of the hard (boney) callus. The RANK-RANKL axis has a central role in the differentiation, maturation and activation of bone-resorbing osteoclasts (original magnification 10×).