{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T01:27:09Z","timestamp":1793582829930,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"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":["32271381"],"award-info":[{"award-number":["32271381"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32471378"],"award-info":[{"award-number":["32471378"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016804","name":"Natural Science Foundation of Shenzhen Municipality","doi-asserted-by":"publisher","award":["JCYJ20220530145601004"],"award-info":[{"award-number":["JCYJ20220530145601004"]}],"id":[{"id":"10.13039\/100016804","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":[[2026,9,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Heterotopic ossification (HO) of the Achilles tendon induces pain and impairs tendon mechanical function, yet its pathogenic mechanisms remain largely unknown. Given that neurotransmitters, inflammatory cytokines, and mechanical loading are highly associated with HO incidence, we raised a hypothesis that activation of sensory neurons within the injured Achilles tendon may be one critical cause driving HO progression. This present work demonstrates that Netrin\u20101, predominantly secreted by macrophages at the injured site, profoundly promotes the regeneration of Piezo2\u2010expressing sensory nerves in the Achilles tendon of mice after puncture. This is accompanied by an aberrant rise in the pro\u2010osteogenic neuropeptide calcitonin gene\u2010related peptide (CGRP) in both sensory nerves at the injury site and the dorsal root ganglion (DRG), particularly under the synergistic influence of mechanical stimulation and prostaglandin E2 (PGE2), a pro\u2010inflammatory cytokine initially produced by macrophages. Consequently, osteogenic differentiation of tendon\u2010derived stem cells (TDSCs) is enhanced, which in turn further stimulates PGE2 secretion from osteoblasts. Of note, such an effect and subsequent HO formation can be significantly attenuated by tail suspension treatment or by blocking signaling pathways mediated by CGRP, Netrin\u20101, PGE2, or Piezo2. Together, these findings elucidate the crosstalk among macrophages, osteoblasts, and Piezo2\n                    <jats:sup>+<\/jats:sup>\n                    sensory neurons in the injured Achilles tendon, highlighting the critical role of sensory hyperinnervation in promoting HO progression.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602038rr","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:35:47Z","timestamp":1788456947000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Piezo2\n                    <sup>+<\/sup>\n                    Mechanosensory Neurons Orchestrate Heterotopic Ossification in Achilles Tendon"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4593-6398","authenticated-orcid":false,"given":"Zhaoji","family":"Cai","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weimin","family":"Fu","sequence":"additional","affiliation":[{"name":"Musculoskeletal Research Laboratory, Department of Orthopedics &amp; Traumatology, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong SAR P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keying","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3007-5655","authenticated-orcid":false,"given":"Bingzhe","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengzhi","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiankun","family":"Xu","sequence":"additional","affiliation":[{"name":"Musculoskeletal Research Laboratory, Department of Orthopedics &amp; Traumatology, Faculty of Medicine The Chinese University of Hong Kong  Hong Kong SAR P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Affiliated Zhongshan Hospital of Dalian University  Dalian Liaoning P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningji","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Emergency, Department of Orthopedics, the Second Hospital, Cheeloo College of Medicine Shandong University  Jinan Shandong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shenzhen Campus of Sun Yat\u2010Sen University  Shenzhen Guangdong P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2024.08.024"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay9526"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/2473011419838294"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-04298-z"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomaterials.4c00935"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2015-0365"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2017.7380"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2025.123507"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-024-00392-y"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00544.2022"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2115821119"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2025.123476"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3A1219-697RR"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-67793-1"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08097-7"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.14840"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg7380"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2024.150351"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02988-5"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1225898"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201504657"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-66988-y"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.02.010"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/iep.12028"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41368-025-00374-8"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18030491"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07495-1"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.22806"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2025.01.034"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4162"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep29824"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.033"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-020-01888-4"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77455"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1177\/0363546509355402"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.23833"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn0532"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28203-0"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2024.09.005"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.05.015"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adm8454"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.33594\/000000713"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2012.07.014"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00494-9"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00969.2001"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-022-03213-3"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.325"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202602038RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202602038RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202602038RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T00:50:53Z","timestamp":1793580653000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202602038RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":47,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2026,9,15]]}},"alternative-id":["10.1096\/fj.202602038RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202602038rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"assertion":[{"value":"2026-04-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e72258"}}