Characterization of Brown Adipose–Like Tissue in Trauma-Induced Heterotopic Ossification in Humans

Abstract

Heterotopic ossification (HO), the abnormal formation of bone within soft tissues, is a major complication after severe trauma or amputation. Transient brown adipocytes have been shown to be a critical regulator of this process in a mouse model of HO. In this study, we evaluated the presence of brown fat within human HO lesions. Most of the excised tissue samples displayed histological characteristics of bone, fibroproliferative cells, blood vessels, and adipose tissue. Immunohistochemical analysis revealed extensive expression of uncoupling protein 1 (UCP1), a definitive marker of brown adipocytes, within HO-containing tissues but not normal tissues. As seen in the brown adipocytes observed during HO in the mouse, these UCP1 cells also expressed the peroxisome proliferator-activated receptor γ coactivator 1α. However, further characterization showed these cells, like their mouse counterparts, did not express PR domain containing protein 16, a key factor present in brown adipocytes found in depots. Nor did they express factors present in beige adipocytes. These results identify a population of UCP1 cells within human tissue undergoing HO that do not entirely resemble either classic brown or beige adipocytes, but rather a specialized form of brown adipocyte-like cells, which have a unique function. These cells may offer a new target to prevent this unwanted bone.

Is heterotopic ossification getting nervous?: The role of the peripheral nervous system in heterotopic ossification

“…Surprisingly, one of the first steps observed in early neurogenic HO (even prior to the appearance of bone matrix) is the biogenesis of brown adipocyte-like cells (tBAT) [81, 82, 83]. BAT is a unique form of adipose tissue induced by cold exposure with the unique feature that it expresses uncoupling protein 1 (UCP1) in mitochondria that uncouples the ATPase from the other complexes of electron transport.…”

Trauma-Induced Heterotopic Ossification Regulates the Blood-Nerve Barrier

“…At the same time, brown adipogenesis was occurring ( 17 ), and the newly formed adipocytes expressed uncoupling protein 1 (UCP1), a hall mark of brown adipose tissue. Recently, we reported that these same cells were present in humans during early HO associated with traumatic injury ( 18 ).…”

“…tBAT is an energy powerhouse and uses UCP1 to create a hypoxic microenvironment for chondrogenesis ( 27 ), but also secretes angiogenic molecules ( 28 ). We have recently described its presence in humans ( 18 ). tBAT and chondrocytes appear closely related and tBAT clearly arises from the endoneurium ( 26 ), yet traverses through the perineurium ( 17 ).…”

“…There are quite a few cells that are key regulators of HO that do not participate in either bone or cartilage formation nor its turnover. Key among these is tBAT ( 17 , 18 , 27 ). The number of these cells increases 70-fold from Day 0 to Day 2 after BMP2 induction and then decrease to baseline after day 4 ( 17 ).…”

“…These cells can control the oxygen tension in the microenvironment because they produce UCP1. Unlike the standard ATPase in the electron transport chain, UCP1 has a very high catalytic rate making it one of the few proteins that can actually burn microenvironmental oxygen ( 18 , 27 ). Therefore, the pattern of hypoxia in the tissue matches exactly the pattern of tBAT ( 27 ).…”