{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T00:47:00Z","timestamp":1794617220880,"version":"4.9.1"},"reference-count":52,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81902179"],"award-info":[{"award-number":["81902179"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20221241"],"award-info":[{"award-number":["BK20221241"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018556","name":"Science and Technology Program of Suzhou","doi-asserted-by":"publisher","award":["SKJY2021094"],"award-info":[{"award-number":["SKJY2021094"]}],"id":[{"id":"10.13039\/501100018556","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Recent advancements in therapeutics have extended lifespan and improved neurodevelopmental outcomes in spinal muscular atrophy (SMA) patients, particularly with severe phenotypes. However, most patients fail to achieve normal motor function. Although structural bone defects and increased fracture susceptibility have been reported in both SMA patients and mouse models, the role of survival motor neuron (SMN) protein in bone homeostasis and therapeutic targets remains incompletely understood. To investigate the function of SMN in bone metabolism, a mild SMA mouse model and\n                    <jats:italic>Smn1<\/jats:italic>\n                    conditional knockout mice in the myeloid lineage and mature osteoclasts were utilized. Bone architecture was assessed using micro\u2010computed tomography (micro\u2010CT), histological staining, and immunohistochemistry. RNA sequencing was performed to explore molecular mechanisms underlying skeletal defects. Primary bone marrow mesenchymal stem cells (BMSCs) and bone marrow\u2010derived macrophages (BMMs) were differentiated into osteoblasts and osteoclasts, respectively, and co\u2010cultured to evaluate SMN\u2010dependent regulation of osteoblast\u2013osteoclast interactions. The therapeutic potential of exogenous osteoprotegerin (OPG) administration was further assessed. SMA mice exhibited significant bone mass reduction, characterized by impaired osteogenesis and increased osteoclastogenesis. However, in\u00a0vitro experiments revealed suppressed osteoclast differentiation in BMMs from SMA mice, which was inconsistent with in\u00a0vivo findings. Co\u2010culture studies demonstrated that osteoclast hyperactivity in SMA mice resulted from decreased osteoblast\u2010derived OPG, induced by local insulin\u2010like growth factor 1 (IGF1) deficiency. Mechanistically, SMN depletion led to IGF1 downregulation, thereby suppressing PI3K\u2010Akt signaling, reducing OPG expression, and ultimately disrupting osteoblast\u2013osteoclast coupling. Administration of exogenous OPG effectively mitigated osteoclast differentiation and resorptive activity, indirectly promoting osteoblast function and partially restoring bone formation. These findings reveal that SMN protein loss caused IGF1 deficiency that inhibited the PI3K\u2010Akt signaling pathway, leading to downregulation of OPG expression and disrupted osteoblast\u2013osteoclast coupling. This study highlights the therapeutic potential of targeting OPG in SMA to alleviate skeletal complications and improve patient outcomes.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501626r","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T01:38:59Z","timestamp":1760405939000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Loss of\n                    <scp>SMN<\/scp>\n                    Impairs Osteoblast\u2013Osteoclast Coupling via\n                    <scp>IGF1<\/scp>\n                    \u2013Akt\u2013\n                    <scp>OPG<\/scp>\n                    Axis in Spinal Muscular Atrophy"],"prefix":"10.1096","volume":"39","author":[{"given":"Taiyang","family":"Xiang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinxuan","family":"Suo","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurology Children's Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7729-9248","authenticated-orcid":false,"given":"Lei","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2217\/fnl-2018-0008"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.18.9920"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.11.002"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90460-3"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)92206-7"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.11.6307"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx166"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.03.034"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80367-0"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80368-2"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2018.4"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.03.031"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt612"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3534-15.2016"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4561"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241511939"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2024.10.015"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.92731.3"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00402-010-1096-1"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2566"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073807305664"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-830366"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2015.05.039"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2017.01.019"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073807299954"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.03.100"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199812)177:4<636::AID-JCP14>3.0.CO;2-H"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa145"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1941310"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-11-271"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2024.116501"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S454116"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.08.021"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20163964"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.279091"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-019-0136-2"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1847"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S275553"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.256644.114"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9092073"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1080\/03008207.2017.1290085"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.139.3.5837"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.9.1260"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1928"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80209-3"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101574"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12470"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2003.18.5.852"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2007-0036"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2024.07.008"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10485"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3233\/JND-230011"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202501626R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202501626R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202501626R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:53:48Z","timestamp":1791276828000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202501626R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":52,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2025,10,31]]}},"alternative-id":["10.1096\/fj.202501626R"],"URL":"https:\/\/doi.org\/10.1096\/fj.202501626r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]},"assertion":[{"value":"2025-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71095"}}