Challenges of heterotopic ossification—Molecular background and current treatment strategies

Abstract

Heterotopic ossification (HO) is an abnormal formation of mature lamellar bone within extraskeletal soft tissues, such as muscles, tendons, and ligaments. This process is thought to be induced by inflammation associated with tissue injuries. HO is classified using two subtypes: resulting from injury or genetically inherited. HO formation is associated with polytrauma patients with traumatic brain injuries and spinal cord injuries. Moreover, HO is also considered to be a post-operative risk factor in some orthopaedic procedures. In this review, we summarize our current understanding of the pathology of different types of HO and discuss its current and future therapies. Thus far, research has revealed cellular and molecular pathways leading to HO formation and proposed several possible mechanisms leading to HO and conserved signalling pathways common in the different HO subtypes. Non-steroidal anti-inflammatory drug treatment and localized low-dose irradiation are currently the only available prophylactic treatments for HO. However, they are not always effective and do not target the osteogenic processes directly. New therapeutic strategies targeting the pathological processes of HO, such as bone morphogenetic protein (BMP) inhibitors like noggin, BMP type 1 receptor inhibitor, and nuclear retinoid acid receptor-gamma (RARγ) agonists, are currently being investigated. In-depth understanding of the HO pathological process could help to develop effective therapeutic strategies.

Heterotopic ossification after central nervous system injuries: understanding of pathogenesis

“…Промежуточная зона окружает центральную зону, которая состоит из недифференцированных фибробластов с участками кровоизлияний и некрозом мышечной ткани. По мере созревания оссификата периферический край промежуточной зоны становится видимым при рентгенологическом исследовании вследствие прогрессирующей минерализации [12]. Весь процесс формирования гетеротопической кости обычно завершается в течение 6-18 мес.…”

The Survey of Cells Responsible for Heterotopic Ossification Development in Skeletal Muscles—Human and Mouse Models

“…The animal studies suggest that progenitor cells can vary depending on the HO subtype. The studies using mouse HO models show that endothelial cells, mesenchymal cells, pericytes present in the skeletal muscles, tendons and connective tissue cells, or even circulating stem/precursor cells could be a source of HO precursors [ 1 , 4 , 5 ]. It is also known, that trauma or micro-trauma, which leads to a local inflammatory response, delivers the signals to develop HO.…”

Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

“…Heterotopic ossification (HO), 1–3 acquired or hereditary, is characterized by pathological bone formation outside of the normal skeleton, generally following tissue damage. For example, acquired HO (aHO), is commonly triggered by traumatic brain injury, spinal cord injury, 4,5 total hip arthroplasty, 6 wartime trauma, or other traumatic injuries. 4,5,7 Following the acute injury, these patients typically develop persistent low-grade inflammation, chronic pain, unhealed wounds, restricted joint movement, nerve entrapment, and diminished quality of life.…”

“…For example, acquired HO (aHO), is commonly triggered by traumatic brain injury, spinal cord injury, 4,5 total hip arthroplasty, 6 wartime trauma, or other traumatic injuries. 4,5,7 Following the acute injury, these patients typically develop persistent low-grade inflammation, chronic pain, unhealed wounds, restricted joint movement, nerve entrapment, and diminished quality of life. Hereditary HO, such as fibrodysplasia ossificans progressiva (FOP), 8 though rare, is much more devastating and life threatening.…”