Inflammation, Bone Healing and Osteonecrosis: From Bedside to Bench

Abstract

Osteonecrosis of the epiphyseal and metaphyseal regions of major weight-bearing bones of the extremities is a condition that is associated with local death of bone cells and marrow in the afflicted compartment. Chronic inflammation is a prominent feature of osteonecrosis. If the persistent inflammation is not resolved, this process will result in progressive collapse and subsequent degenerative arthritis. In the pre-collapse stage of osteonecrosis, attempt at joint preservation rather than joint replacement in this younger population with osteonecrosis is a major clinical objective. In this regard, core decompression, with/without local injection of bone marrow aspirate concentrate (BMAC), is an accepted and evidence-based method to help arrest the progression and improve the outcome of early-stage osteonecrosis. However, some patients do not respond favorably to this treatment. Thus, it is prudent to consider strategies to mitigate chronic inflammation concurrent with addressing the deficiencies in osteogenesis and vasculogenesis in order to save the affected joint. Interestingly, the processes of inflammation, osteonecrosis, and bone healing are highly inter-related. Therefore, modulating the biological processes and crosstalk among cells of the innate immune system, the mesenchymal stem cell-osteoblast lineage and others are important to providing the local microenvironment for resolution of inflammation and subsequent repair. This review summarizes the clinical and biologic principles associated with osteonecrosis and provides potential cutting-end strategies for modulating chronic inflammation and facilitating osteogenesis and vasculogenesis using local interventions. Although these studies are still in the preclinical stages, it is hoped that safe, efficacious, and cost-effective interventions will be developed to save the host's natural joint.

Keywords: bone healing; chronic inflammation; inflammation; osteogenesis; osteonecrosis; vasculogenesis.

Figure 1

Pathophysiology of osteonecrosis. Numerous etiologies are associated with osteonecrosis. However, the final common pathophysiologic pathway involves inadequate oxygen and nutrient supply to the affected area. These events lead to enhanced differentiation of MSCs along the adipogenic pathway, and deficient osteogenesis and vasculogenesis. Osteonecrosis also demonstrates signs of chronic inflammation: persistent accumulation of activated neutrophils, macrophages, T cells, and other cell types; continued activation of TLR4, MyD88, and NF-kB; increased production of pro-inflammatory mediators.

Figure 2

Potential therapeutic approaches for the resolution of chronic inflammation. Acute inflammation is necessary for healing of tissues after injury. However, chronic inflammation is detrimental, and leads to loss of tissue integrity and function. Potential avenues for mitigation of chronic inflammation are listed.

Figure 3

Potential approaches for local delivery of biomolecules, cell therapies, and gene therapies to enhance osteogenesis and vasculogenesis in osteonecrosis.