{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:30:44Z","timestamp":1768509044581,"version":"3.49.0"},"posted":{"date-parts":[[2024,3,4]]},"group-title":"Cancer Biology","reference-count":42,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Adult T cell leukemia (ATL), caused by infection with human T cell leukemia virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV\/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV\/T lead to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV\/T cells persisted in the bone. To study the direct effect of HTLV\/T and ATL-PDX on osteoclasts, supernatants were added to murine and human osteoclast precursors. ATL-PDX supernatants from hypercalcemic patients promoted formation of mature osteoclasts, while those from HTLV\/T were variably stimulatory, but had largely consistent effects between human and murine cultures. Interestingly, this osteoclastic activity did not correlate with expression of osteoclastogenic cytokine RANKL, suggesting an alternative mechanism. HTLV\/T and ATL-PDX produce small extracellular vesicles (sEV), known to facilitate HTLV-1 infection. We hypothesized that these sEV also mediate bone loss by targeting osteoclasts. We isolated sEV from both HTLV\/T and ATL-PDX, and found they carried most of the activity found in supernatants. In contrast, sEV from uninfected activated T cells had little effect. Analysis of sEV (both active and inactive) by mass spectrometry and electron microscopy confirmed absence of RANKL and intact virus. Viral proteins Tax and Env were only present in sEV from the active, osteoclast-stimulatory group, along with increased representation of proteins involved in osteoclastogenesis and bone resorption. sEV injected over mouse calvaria in the presence of low dose RANKL caused more osteolysis than RANKL alone. Thus, HTLV-1 infection of T cells can cause release of sEV with strong osteolytic potential, providing a mechanism beyond RANKL production that modifies the bone microenvironment, even in the absence of overt leukemia.<\/jats:p>","DOI":"10.1101\/2024.02.29.582779","type":"posted-content","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T12:35:11Z","timestamp":1709555711000},"source":"Crossref","is-referenced-by-count":0,"title":["HTLV-1 infected T cells cause bone loss via small extracellular vesicles"],"prefix":"10.64898","author":[{"given":"Nitin Kumar","family":"Pokhrel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Panfil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haniya","family":"Habib","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sham","family":"Seeniraj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ancy","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Rauch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Cox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Sprung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra Erdmann","family":"Gilmore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R Reid","family":"Townsend","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianbo","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayse Selen","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajeev","family":"Aurora","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee","family":"Ratner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine N","family":"Weilbaecher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah J","family":"Veis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024030610000666000_2024.02.29.582779v1.1","doi-asserted-by":"publisher","DOI":"10.1200\/JOP.2017.021907"},{"key":"2024030610000666000_2024.02.29.582779v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19870315)59:6<1187::AID-CNCR2820590626>3.0.CO;2-8"},{"issue":"5-6","key":"2024030610000666000_2024.02.29.582779v1.3","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3109\/10428199409049695","article-title":"Hypercalcemia, parathyroid hormone-related protein expression and human T-cell leukemia virus infection","volume":"14","year":"1994","journal-title":"Leuk Lymphoma"},{"issue":"19","key":"2024030610000666000_2024.02.29.582779v1.4","first-page":"100257","article-title":"Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia\/lymphoma in bone","volume":"20","year":"2019","journal-title":"J Bone Oncol"},{"issue":"4","key":"2024030610000666000_2024.02.29.582779v1.5","doi-asserted-by":"crossref","first-page":"702","DOI":"10.3109\/10428191003646697","article-title":"Osteolytic bone resorption in adult T-cell leukemia\/lymphoma","volume":"51","year":"2010","journal-title":"Leuk Lymphoma"},{"key":"2024030610000666000_2024.02.29.582779v1.6","doi-asserted-by":"crossref","unstructured":"Xiang J , Rauch DA , Huey DD , Panfil AR , Cheng X , Esser AK , et al. 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