{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:01:27Z","timestamp":1790182887519,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Uterine Sensitization-Associated Gene-1 (USAG-1), also known as SOSTDC1, is a bifunctional antagonist of bone morphogenetic protein (BMP) and Wnt signalling\u2014two pathways that are central not only to tooth development but to the entire repertoire of periodontal tissue biology. Current periodontal regenerative therapy relies on exogenous BMP delivery and barrier membranes, approaches with significant limitations in predictability and tissue specificity. The recent entry of anti-USAG-1 antibody therapy into early-phase human clinical trials, with congenital tooth agenesis as the lead indication, raises the question of whether targeted USAG-1 inhibition could be repurposed for periodontal regeneration. Purpose: This perspective examines the biological rationale for USAG-1 as a target in periodontal regeneration, maps the plausible mechanisms through which its inhibition could restore cementum, periodontal ligament (PDL), and alveolar bone, and outlines the conditions and research agenda under which such an approach could be clinically developed. Conclusions: USAG-1 transcripts have been reported in adult gingival tissues, and USAG-1 antagonises BMP and Wnt signals that are implicated in cementogenesis, PDL fibre formation, and alveolar bone homeostasis. Its inhibition is proposed as a biologically plausible, hypothesis-generating strategy for amplifying endogenous regenerative signalling in the periodontium, which might differ from, and could potentially complement, existing regenerative protocols; neither possibility has yet been tested. Realising this potential will require localised delivery strategies, validated biomarker endpoints, and controlled trials embedded in the framework of the EFP S3 stepwise treatment algorithm. Direct experimental evidence that USAG-1 inhibition promotes periodontal regeneration is currently lacking; the case advanced here is inferential and hypothesis-generating, not a demonstrated therapeutic effect.<\/jats:p>","DOI":"10.3390\/molecules31193389","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:10:31Z","timestamp":1790179831000},"page":"3389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["USAG-1\/SOSTDC1 as a Candidate Target for Periodontal Regeneration: Biological Rationale, Knowledge Gaps, and Future Directions"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5485-2768","authenticated-orcid":false,"given":"Nada Tawfig","family":"Hashim","sequence":"first","affiliation":[{"name":"Department of Periodontics, RAK College of Dental Sciences, RAK Medical & Health Sciences University, Ras-Al Khaimah 12973, United Arab Emirates"},{"name":"Department of Oral Rehabilitation, Faculty of Dentistry, University of Khartoum, Khartoum 11115, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakri Gobara","family":"Gismalla","sequence":"additional","affiliation":[{"name":"Department of Oral Rehabilitation, Faculty of Dentistry, University of Khartoum, Khartoum 11115, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayman","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Periodontology and Implantology, College of Dentistry, The National Ribat University, Khartoum 11115, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed Mustahsen","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Periodontics, RAK College of Dental Sciences, RAK Medical & Health Sciences University, Ras-Al Khaimah 12973, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Padmanabhan","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Preventive Dentistry, RAK College of Dental Sciences, RAK Medical & Health Sciences University, Ras-Al Khaimah 12973, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0604-9553","authenticated-orcid":false,"given":"Md Sofiqul","family":"Islam","sequence":"additional","affiliation":[{"name":"Department of Operative Dentistry, RAK College of Dental Sciences, RAK Medical & Health Sciences University, Ras-Al Khaimah 12973, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3017-6245","authenticated-orcid":false,"given":"Riham","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery, RAK College of Dental Sciences, RAK Medical & Health Sciences University, Ras-Al Khaimah 12973, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Elsheikh","sequence":"additional","affiliation":[{"name":"Department of Oral &Maxillofacial Surgery, Faculty of Dentistry, University of Khartoum, Khartoum 11115, Sudan"},{"name":"Clinical Sciences Department, College of Dentistry, Ajman University, Ajman P.O. Box 346, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7302-7261","authenticated-orcid":false,"given":"Shadi","family":"El Bahra","sequence":"additional","affiliation":[{"name":"Clinical Sciences Department, College of Dentistry, Ajman University, Ajman P.O. Box 346, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S149","DOI":"10.1111\/jcpe.12945","article-title":"Staging and grading of periodontitis: Framework and proposal of a new classification and case definition","volume":"45","author":"Tonetti","year":"2018","journal-title":"J. Clin. 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