What the paper is
Hashim and colleagues, affiliated with RAK Medical and Health Sciences University in the UAE, the University of Khartoum and National Ribat University in Sudan, and Ajman University, published a perspective in Molecules on 23 September 2026 that asks a question the anti-USAG-1 field has not formally addressed: if blocking USAG-1 can induce new tooth formation, could local USAG-1 inhibition also regenerate the tissues that hold a tooth in place, namely cementum, periodontal ligament, and alveolar bone (DOI 10.3390/molecules31193389, received 19 August 2026, accepted 22 September 2026). It is a hypothesis paper, not a study: the authors state that no new data were created or analyzed, and they grade every central claim in a table as established biology, indirect evidence, or hypothesis. Their own conclusion sentence is blunt: direct experimental evidence that USAG-1 inhibition promotes periodontal regeneration is currently lacking, and the case is inferential, not a demonstrated therapeutic effect.
The rationale, as far as it goes
USAG-1 (SOSTDC1) is a secreted protein that antagonizes both BMP and Wnt signaling, and it is the target of Toregem BioPharma’s antibody TRG-035. The paper assembles three building blocks. First, BMP and Wnt signaling drive cementoblast differentiation, periodontal ligament stem cell behavior, and alveolar bone homeostasis, and exogenous BMP delivery is already the basis of existing regenerative attempts, with known limits: high-dose rhBMP-2 is documented to cause root resorption and ankylosis, and in human periodontal ligament stem cells in vitro the lineage effect of BMP-4 is dose-dependent, with 10 ng/mL sustaining multipotency and 100 ng/mL favoring ligament-like over bone-like differentiation, so the direction of any shift cannot be predicted from more signaling alone. Second, a 2026 single-cell reanalysis of public transcriptomic data (Moradi et al.) reports USAG-1 transcripts in adult human gingival fibroblast subsets and basal gingival epithelial cells, but only in non-diseased tissue, and only at the transcript level. Third, the closest in-periodontum proof of principle is a different Wnt antagonist: osteocyte-specific deletion of Dkk-1 reduced alveolar bone loss by 28.5% in a murine ligature-induced periodontitis model (Goes et al. 2019), which shows that modulating a Wnt antagonist can move alveolar bone biology in a mouse. The paper is careful to state that USAG-1 and Dkk-1 are not interchangeable, and that the 28.5% figure is not a quantitative prediction for anti-USAG-1 therapy.
What it would take
The authors argue systemic intravenous delivery, the model used in the TRG-035 tooth-agenesis trials, is the wrong route for a periodontal application, both because the effect must be local and because USAG-1 has physiological roles in renal BMP signaling that make systemic blockade a safety concern. They propose four delivery strategies (antibody in a collagen membrane or on a graft carrier, local gene silencing, and small-molecule inhibitors, the last so far existing only as a non-peer-reviewed computational preprint) and a six-step research agenda that starts with the missing baseline experiment, protein-level mapping of USAG-1 in periodontitis versus healthy tissue, before any animal work. Their proposed first animal study is a ligature-induced periodontitis model with local antibody delivery at flap surgery and regenerative endpoints at 8 and 16 weeks, with renal histopathology as a mandatory safety readout. They position the approach, if it ever works, as a Step 3 adjunct to surgery inside the EFP S3 stepwise treatment algorithm, not a replacement for inflammation control, noting that unresolved inflammation through TNF-alpha, IL-1beta, and LPS would likely neutralize any anabolic BMP or Wnt stimulus.
Where it sits in the field
For the anti-USAG-1 / TRG-035 program, this is the first peer-reviewed attempt we know of to extend the antibody’s rationale beyond tooth induction into a second indication, periodontal regeneration. It also confirms, from outside the sponsor, the program’s public status as of late September 2026: the paper notes that first-in-human testing reportedly began in late 2024, that sponsor announcements indicate completion of that trial and preparation of a phase IIa study, and that the authors found no peer-reviewed report of the clinical results at the time of writing. On this site’s ledger the program remains where it was: human safety data disclosed only by sponsor materials, no public evidence of tooth induction in a person, and this perspective adds a credible argument that even the periodontal offshoot is one experiment away from having any direct evidence. The current field assessment stands at /field/.
Where we differ from the coverage
We found no press or popular coverage of this paper to differ from. Against the paper’s own framing, we hold back one inference a reader could easily make: the strongest quantitative number in it, the 28.5% reduction in bone loss, belongs to Dkk-1 deletion in mice, not to USAG-1 blockade, and the authors themselves refuse to transfer it. It is also tempting to read a periodontal application as a nearer-term use of TRG-035 than tooth regeneration, but this paper is a research agenda whose step one experiment, confirming USAG-1 protein expression in diseased periodontal tissue, has not been done, so the honest distance to any periodontal trial is longer than the existence of the antibody suggests.
Provenance: every claim above is grounded in the full text of Hashim et al. 2026, retrieved from Europe PMC (PMC13666155) on 18 October 2026. Method: /method/.