Impact of Therapeutic Irradiation on Healthy Articular Cartilage

Abstract

Radiation-induced complications in bone and cartilage are of increasing concern due to potential long-term effects in cancer survivors. Healthy articular cartilage may be exposed to radiation during either chondrosarcoma treatment or in-field radiotherapy of tumors located in close proximity to articulation. Cartilage exposed to radiation undergoes bone differentiation and senescence, which can lead to painful and disabling sequelae that can impair patient quality of life. An understanding of the biological processes involved in healthy cartilage response to radiotherapy may not only optimize the delivery of therapeutic radiation but also reduce the risk of long-term sequelae in irradiated cartilage. Over the last few decades, radiobiology studies have focused primarily on signaling and repair of DNA damage pathways induced by ionizing radiation in immortalized cells under conditions dramatically different from human homeostasis. This research needs to be continued and broadened, since the range of normal tissue responses to radiation exposure is still not fully understood, despite being recognized as the major limiting factor in the rupture of tissue homeostasis after radiotherapy. Human articular cartilage is an avascular tissue with low intracellular oxygen levels and is comprised of a single cell lineage of chondrocytes embedded in a highly dense and structured extracellular matrix. These relatively unique features may impact inherent cell radiation sensitivity and suggests that canonical cell responses to ionizing radiation may not be applicable to articular cartilage. Despite the number of studies in this field, radiation-induced modifications of chondrocyte proteome remain unclear because of the dramatic variability in reported experimental conditions. In this review, we propose to introduce cartilage tissue physiology and microenvironment concepts, and then present a comprehensive synthesis of cartilage radiation biology.

Comparable Senescence Induction in Three-dimensional Human Cartilage Model by Exposure to Therapeutic Doses of X-rays or C-ions

“…Monolayer 2D culture of HACs was used as a control. Very few studies have been published on the survival of HACs after IR exposure (6). The data analysis of D 10 survival after X-ray irradiation (4.1 Gy) showed a rather higher value (2.7 Gy) than previously reported (29).…”

“…Depending on the cell lines, it can be triggered by low or very high doses of IR (27). Moreover, human mesenchymal cells (precursors of chondrocytes), in contrast to arthritic chondrocytes, do not undergo radiation-induced apoptosis, probably owing to the efficient activation of the DNA damage response pathways (6,33). Furthermore, our results have shown that C-ion irradiation induced twice as much SA-b-Galepositive cells in 2D culture compared with X-ray irradiation (Fig.…”

“…Senescence has been suggested as a potential mechanism to explain low-LETeinduced cartilage attrition and osteoarthritis in the clinic (6). We investigated the differential senescence induction of C-ions versus X-rays in 3DCaM and 2D HACs.…”

“…It has been hypothesized that the senescence induced by cancer therapy is implicated in the organ deterioration experienced by patients surviving cancer and leading to a poor quality of life (5). Hyaline articular cartilage can be side-exposed to ionizing radiation (IR), which might induce bone differentiation and senescence (6). The senescence of chondrocytes has been defined as the "age-dependent deterioration of chondrocytes following intrinsic and extrinsic factors" (7).…”

Hondroplastic Efficiency of Calcified Bone Matrix Produced by Original Technology

“…(9) The advent of tissue engineering techniques has provided alternative options for treating such patients by using cellular therapy in combination with synthetic extracellular matrix substitutes and biologically active factors for the functional replacement of articular hyaline cartilage. (10) This study showed that the bone matrix granules, when implanted into the articular cartilage defect zone, have a pronounced chondromodulatory effect, prolonged by activating reparative chondrogenesis. In the area of damage to the articular cartilage in the early period, a regenerate is formed, acquiring the cellular specificity of the hyaline cartilaginous tissue.…”