The C-Terminal Intact Forms of Periostin (iPTN) Are Surrogate Markers for Osteolytic Lesions in Experimental Breast Cancer Bone Metastasis

Abstract

Periostin is an extracellular matrix protein that actively contributes to tumor progression and metastasis. Here, we hypothesized that it could be a marker of bone metastasis formation. To address this question, we used two polyclonal antibodies directed against the whole molecule or its C-terminal domain to explore the expression of intact and truncated forms of periostin in the serum and tissues (lung, heart, bone) of wild-type and periostin-deficient mice. In normal bones, periostin was expressed in the periosteum and specific periostin proteolytic fragments were found in bones, but not in soft tissues. In animals bearing osteolytic lesions caused by 4T1 cells, C-terminal intact periostin (iPTN) expression disappeared at the invasive front of skeletal tumors where bone-resorbing osteoclasts were present. In vitro, we found that periostin was a substrate for osteoclast-derived cathepsin K, generating proteolytic fragments that were not recognized by anti-periostin antibodies directed against iPTN. In vivo, using an in-house sandwich immunoassay aimed at detecting iPTN only, we observed a noticeable reduction of serum periostin levels (- 26%; P < 0.002) in animals bearing osteolytic lesions caused by 4T1 cells. On the contrary, this decrease was not observed in women with breast cancer and bone metastases when periostin was measured with a human assay detecting total periostin. Collectively, these data showed that mouse periostin was degraded at the bone metastatic sites, potentially by cathepsin K, and that the specific measurement of iPTN in serum should assist in detecting bone metastasis formation in breast cancer.

Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment

“…Finally, cathepsin K was demonstrated to cleave periostin, which may be linked to breast cancer bone metastasis. The decrease of C-terminal intact periostin was namely shown to be a marker for osteolytic lesions in breast cancer bone metastasis and could be used to detect bone relapse in patients [89]. Cathepsin K cleavage of osteonectin was also implicated in experimental prostate to bone tumor metastasis, where both the protease and substrate expression levels were higher.…”

Periostin in Osteoporosis and Cardiovascular Disease

“…Postn has been suggested as a biomarker of numerous bone conditions including cortical bone metabolism [ 19 ], chondrosarcoma [ 58 ], arthritis [ 38 ], fibrous dysplasia of bone severity [ 59 ], and a surrogate marker for osteolytic lesions in breast cancer [ 60 ]. Postn is a good marker of cortical porosity [ 61 ], as its serum concentration increases with cortical porosity in conditions of mechanical stress under gravity.…”

Osteosarcoma Cell-Derived Small Extracellular Vesicles Enhance Osteoclastogenesis and Bone Resorption Through Transferring MicroRNA-19a-3p

“…OS is clinically characterized by extensive bone destruction and metastasis in which osteoclasts play essential roles (23)(24)(25)(26). It was reported that osteoclasts are responsible for bone destruction and metastasis in bone metastases (5). Herein, osteoclast could be a target both in bone destruction and cancer progression.…”

“…Thus, it is urgent to explore new targets for OS therapies (4). It is well established that osteoclasts are responsible for bone destruction in cancer bone metastasis such as breast cancer and prostate cancer and this is necessary for tumor expansion within the bone (5)(6)(7). And in OS progression, osteoclasts are believed to play a crucial role.…”