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

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

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: shufenglisd@126.com.
  • 5 Shandong University of Traditional Chinese Medicine Second Affiliated Hospital, Jinan, 250001, People's Republic of China. Electronic address: liyujie.11@163.com.
  • 6 Shandong University of Traditional Chinese Medicine Second Affiliated Hospital, Jinan, 250001, People's Republic of China. Electronic address: wangvenbo@126.com.
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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