Pilose antler peptide enhances diabetic fracture healing by modulating the CREB-Smad2/3-Runx2 signaling axis

  • J Ethnopharmacol. 2025 Aug 30:354:120514. doi: 10.1016/j.jep.2025.120514.
Xin Wang  1 ,  Yibing Chen  1 ,  Ziyang Cheng  1 ,  Zhong Cao  2 ,  ShuChao Cheng  2 ,  Chao Xin  3 ,  Jiayi Zhang  1 ,  Fengyi Zhang  1 ,  Yaxin Chen  1 ,  Junyi Wang  1 ,  Shufeng Li  4 ,  Yujie Li  5 ,  Wenbo Wang  6
Affiliations
  • 1. Shandong University of Traditional Chinese Medicine First Clinical Medical College, Jinan, 250014, People's Republic of China.
  • 2. Shandong University of Traditional Chinese Medicine Second Affiliated Hospital, Jinan, 250001, People's Republic of China.
  • 3. Affiliated Hospital of Shandong Academy of Traditional Chinese Medicine, Jinan, 250014, People's Republic of China.
  • 4. The First Affiliated Hospital of Shandong First Medical University, Jinan, 250014, People's Republic of China. Electronic address: [email protected].
  • 5. Shandong University of Traditional Chinese Medicine Second Affiliated Hospital, Jinan, 250001, People's Republic of China. Electronic address: [email protected].
  • 6. Shandong University of Traditional Chinese Medicine Second Affiliated Hospital, Jinan, 250001, People's Republic of China. Electronic address: [email protected].
PMID: 40889600 DOI: 10.1016/j.jep.2025.120514
Abstract

Ethnopharmacological relevance: Cervi Cornu Pantotrichum, a cornerstone of traditional medicine, is prized for its bone-enhancing and metabolic-regulating effects. Pilose antler peptide (PAP), extracted from this remedy, offers a promising solution for diabetic fracture nonunion, a debilitating condition marked by hyperglycemia-impaired bone healing.

Aim of the study: This study investigates PAP's efficacy in accelerating diabetic fracture repair and delineates its molecular mechanisms, merging ethnopharmacological heritage with modern science.

Materials and methods: Diabetic fractures were induced in db/db mice, and PAP's effects were evaluated using micro-CT, histology, and osteogenic marker analysis. In vitro, high glucose-treated MC3T3-E1 osteoblasts mimicked diabetic conditions. Molecular mechanisms were probed via co-immunoprecipitation (Co-IP), fluorescence colocalization, molecular docking, and genetic modulation.

Results: PAP markedly improved fracture healing in diabetic mice, enhancing callus integrity, bone microarchitecture, and osteogenic marker levels. In osteoblasts, PAP counteracted high glucose-induced osteogenic suppression, boosting RUNX2 expression while inhibiting CREB and SMAD3 activation. Co-IP revealed PAP's disruption of the CREB-Smad2/3 complex, with colocalization showing diminished nuclear overlap of CREB and SMAD2/3. Molecular docking identified PAP binding to CREB-Arg117 and Smad3-Glu246, supporting its inhibitory role. Genetic studies confirmed PAP's reversal of SMAD2/3-mediated RUNX2 suppression.

Conclusion: PAP alleviates metabolic stress and promotes bone regeneration by targeting the CREB-Smad2/3-Runx2 axis. Rooted in ethnopharmacology, this multitarget peptide integrates traditional wisdom with cutting-edge molecular insights, presenting a novel therapeutic avenue for diabetic fracture management.

Keywords
CREB-Smad2/3-Runx2; Diabetic fracture repair; Osteogenic differentiation; Pilose antler peptide.
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