{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:39:14Z","timestamp":1787755154729,"version":"build-2784847793"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Bone and Joint Surgery"],"published-print":{"date-parts":[[2019,11,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Osteoclasts are hematopoietic stem cell-derived multinucleated cells necessary for bone remodeling and resorption.\n                      <jats:italic toggle=\"yes\">TCIRG1<\/jats:italic>\n                      encodes a protein that is an adenosine triphosphate (ATP)-dependent vacuolar proton pump required for this process. Recessive loss-of-function mutations in both copies of this gene lead to impairment of osteoclast function, with increased bone density, increased skeletal mass, and early mortality.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We isolated fibroblasts from a patient with the compound heterozygous\n                      <jats:italic toggle=\"yes\">TCIRG1<\/jats:italic>\n                      mutations c.1549G&gt;A (p.517D&gt;N) and c.2236C&gt;T (p.746Q&gt;X), and reprogrammed them into iPS (induced pluripotent stem) cells. The function of osteoclasts derived from these cells was then rescued by transgenic expression of\n                      <jats:italic toggle=\"yes\">TCIRG1<\/jats:italic>\n                      cDNA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      In addition to the known effects of\n                      <jats:italic toggle=\"yes\">TCIRG1<\/jats:italic>\n                      loss of function, iPS cell-derived osteoclasts from this patient had reduced expression of the bone remodeling enzymes cathepsin K\n                      <jats:italic toggle=\"yes\">(CTSK)<\/jats:italic>\n                      and tartrate-resistant acid phosphatase\n                      <jats:italic toggle=\"yes\">(TRAP),<\/jats:italic>\n                      leading to reduced in vitro bone remodeling. Expression of both genes and pit formation were restored in iPS cell-derived osteoclasts following transgenic restoration of\n                      <jats:italic toggle=\"yes\">TCIRG1<\/jats:italic>\n                      expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Transgenic overexpression of\n                      <jats:italic toggle=\"yes\">TCIRG1<\/jats:italic>\n                      was sufficient to restore osteoclast function in iPS cell-derived osteoclasts from a patient with infantile malignant autosomal-recessive osteopetrosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Relevance:<\/jats:title>\n                    <jats:p>This work provides a proof of concept for an autologous approach to treating osteopetrosis, potentially avoiding the risks associated with hematopoietic stem cell transplantation in a young patient population.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2106\/jbjs.19.00558","type":"journal-article","created":{"date-parts":[[2019,9,20]],"date-time":"2019-09-20T05:13:16Z","timestamp":1568956396000},"page":"1939-1947","source":"Crossref","is-referenced-by-count":14,"title":["TCIRG1 Transgenic Rescue of Osteoclast Function Using Induced Pluripotent Stem Cells Derived from Patients with Infantile Malignant Autosomal Recessive Osteopetrosis"],"prefix":"10.2106","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1998-5965","authenticated-orcid":false,"given":"Weili","family":"Chen","sequence":"first","affiliation":[{"name":"Stem Cell Institute (W.C., K.T., and J.T.) and Division of Blood and Marrow Transplantation (C.E., M.J.R., P.J.O., and J.T.), Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2384-6298","authenticated-orcid":false,"given":"Kirk","family":"Twaroski","sequence":"additional","affiliation":[{"name":"Stem Cell Institute (W.C., K.T., and J.T.) and Division of Blood and Marrow Transplantation (C.E., M.J.R., P.J.O., and J.T.), Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7314-2550","authenticated-orcid":false,"given":"Cindy","family":"Eide","sequence":"additional","affiliation":[{"name":"Stem Cell Institute (W.C., K.T., and J.T.) and Division of Blood and Marrow Transplantation (C.E., M.J.R., P.J.O., and J.T.), Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9557-217X","authenticated-orcid":false,"given":"Megan J.","family":"Riddle","sequence":"additional","affiliation":[{"name":"Stem Cell Institute (W.C., K.T., and J.T.) and Division of Blood and Marrow Transplantation (C.E., M.J.R., P.J.O., and J.T.), Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9426-1292","authenticated-orcid":false,"given":"Paul J.","family":"Orchard","sequence":"additional","affiliation":[{"name":"Stem Cell Institute (W.C., K.T., and J.T.) and Division of Blood and Marrow Transplantation (C.E., M.J.R., P.J.O., and J.T.), Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0957-4380","authenticated-orcid":false,"given":"Jakub","family":"Tolar","sequence":"additional","affiliation":[{"name":"Stem Cell Institute (W.C., K.T., and J.T.) and Division of Blood and Marrow Transplantation 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