Rotator cuff tears lead to bone loss because of reduced mechanical loading at the tendon-bone interface, which results in poor healing after rotator cuff repair (RCR). Whether Yoda1, the specific Piezo1 agonist, can counteract bone loss and promote rotator cuff healing has not yet been explored.
Hypothesis:
Yoda1 promotes tendon-to-bone healing in a rat model of RCR and regulates M1/M2 macrophage polarization at the tendon-bone interface.
Study Design:
Controlled laboratory study.
Methods:
A total of 120 male rats aged 12 weeks, which were randomly divided into 4 groups, were used to establish the RCR model: vehicle-only (control [CON]), low-concentration Yoda1 (LC), moderate-concentration Yoda1 (MC), and high-concentration Yoda1 (HC) intraperitoneal injection. The rats were sacrificed at 4 and 8 weeks. Tendon-to-bone healing at the repair site was evaluated using histological, bone microstructure, and biomechanical analyses. Macrophage polarization was observed through immunofluorescence staining.
Results:
The LC group showed higher histological scores compared with the CON group at each time point (P < .001). More organized collagen fibers and greater cartilage regeneration were observed in the intervention groups compared with the CON group, as confirmed by immunohistochemistry for collagen type II. Additionally, the LC group exhibited more new bone formation compared to the CON group at 4 weeks (P < .001). Biomechanically, all intervention groups exhibited significantly higher failure loads and stiffness than the CON group at 4 and 8 weeks. In immune regulation, the expression of CD86 was significantly decreased, and CD206 expression was significantly increased, in the intervention groups compared to the CON group at 4 weeks. However, there were no significant differences in the expression of CD86 and CD206 among the groups at 8 weeks.
Conclusion:
Yoda1 improved tendon-to-bone healing in a rat model of RCR. In addition, Yoda1 promoted the infiltration of M2 macrophages at the repair site, which may have facilitated healing at the tendon-bone interface.
Clinical Relevance:
The present study is an exploratory investigation. Postoperative treatment using Yoda1 could be a potential therapeutic strategy to improve tendon-to-bone healing in patients with rotator cuff tears.
AndersonDEBrounKGKunduP, et al. PIEZO1 is downregulated in glenohumeral chondrocytes in early cuff tear arthropathy following a massive rotator cuff tear in a mouse model. Front Bioeng Biotechnol. 2023;11:1244975.
CadetERVorysGCRahmanR, et al. Improving bone density at the rotator cuff footprint increases supraspinatus tendon failure stress in a rat model. J Orthop Res. 2010;28(3):308-314.
4.
CaiGLuYZhongW, et al. Piezo1-mediated M2 macrophage mechanotransduction enhances bone formation through secretion and activation of transforming growth factor-β1. Cell Prolif. 2023;56(9):e13440.
5.
CaiZShuLWangCXieXLiuX.M2 macrophage-derived exosomes promote tendon-to-bone healing by alleviating cellular senescence in aged rats. Arthroscopy. 2025;41(6):1731-1742.e3.
6.
CancienneJMBrockmeierSFKewMEDeaseyMJWernerBC.The association of osteoporosis and bisphosphonate use with revision shoulder surgery after rotator cuff repair. Arthroscopy. 2019;35(8):2314-2320.
7.
ChenWSunYGuX, et al. Conditioned medium of human bone marrow-derived stem cells promotes tendon-bone healing of the rotator cuff in a rat model. Biomaterials. 2021;271:120714.
8.
CongSSunYLinJLiuSChenJ.A synthetic graft with multilayered co-electrospinning nanoscaffolds for bridging massive rotator cuff tear in a rat model. Am J Sports Med. 2020;48(8):1826-1836.
9.
CosteBMathurJSchmidtM, et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010;330(6000):55-60.
10.
DarbandiACredilleKDarbandiA, et al. Fatty infiltration, tear size, and retraction size are significant risk factors for retear after arthroscopic rotator cuff repair: a systematic review. Arthroscopy. 2025;41(5):1649-1666.e3.
11.
DehestaniPFarahmandFBorjaliABashtiKChizariM.Bone density may affect primary stability of anterior cruciate ligament reconstruction when organic core bone plug fixation technique used. J Exp Orthop. 2022;9(1):5.
12.
DongLSongYZhangY, et al. Mechanical stretch induces osteogenesis through the alternative activation of macrophages. J Cell Physiol. 2021;236(9):6376-6390.
13.
DuchmanKRGoetzJEUribeBU, et al. Delayed administration of recombinant human parathyroid hormone improves early biomechanical strength in a rat rotator cuff repair model. J Shoulder Elbow Surg. 2016;25(8):1280-1287.
14.
FengHZhangGXiongL, et al. Functionally graded scaffold with M2 macrophage-derived lncRNA-encoded peptide: mechanistic and therapeutic evaluation for rotator cuff repair. Bioact Mater. 2025;52:668-686.
15.
GanDRanYPanH, et al. The Sirt1-Piezo1 axis promotes bone formation and repair in mice. Adv Sci (Weinh). 2025;12(44):e10103.
16.
GoonSShiu Chen LiuCGhosh DastidarU, et al. Exploring the structural attributes of Yoda1 for the development of new-generation Piezo1 agonist Yaddle1 as a vaccine adjuvant targeting optimal T cell activation. J Med Chem. 2024;67(10):8225-8246.
17.
HeXLiuYDaiZ, et al. Yoda1 pretreated BMSC derived exosomes accelerate osteogenesis by activating phospho-ErK signaling via Yoda1-mediated signal transmission. J Nanobiotechnology. 2024;22(1):407.
18.
HjorthaugGASøreideENordslettenL, et al. Negative effect of zoledronic acid on tendon-to-bone healing. Acta Orthop. 2018;89(3):360-366.
19.
HuJChenQZhuH, et al. Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease. Neuron. 2023;111(1):15-29.e8.
20.
JanhaviPDivyashreeSSanjailalKPMuthukumarSP.DoseCal: a virtual calculator for dosage conversion between human and different animal species. Arch Physiol Biochem. 2022;128(2):426-430.
21.
JohnsonJWvon StadeDGadomskiB, et al. Modified alendronate mitigates mechanical degradation of the rotator cuff in an osteoporotic ovine model. Am J Sports Med. 2022;50(13):3649-3659.
22.
KhanAAMorrisonAHanleyDA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30(1):3-23.
23.
KimDMShimIKShinMJ, et al. A combination treatment of raloxifene and vitamin D enhances bone-to-tendon healing of the rotator cuff in a rat model. Am J Sports Med. 2020;48(9):2161-2169.
24.
KinsellaJADebantMParsonageG, et al. Pharmacology of PIEZO1 channels. Br J Pharmacol. 2024;181(23):4714-4732.
25.
LeeJHYoonJYLeeYB.The use of intravenous zoledronate may reduce retear rate after rotator cuff repair in older female patients with osteoporosis: a first in-human prospective study. J Clin Med. 2022;11(3):836.
26.
LeiLWenZCaoM, et al. The emerging role of Piezo1 in the musculoskeletal system and disease. Theranostics. 2024;14(10):3963-3983.
27.
LinYWenDChenK, et al. Piezo1 and tissue fibrosis: insights into its role and potential for modulation. Burns Trauma. 2025;13:tkaf054.
LiuYZhaoRHuangZ, et al. Association between osteoporosis and rotator cuff tears: evidence from causal inference and colocalization analyses. Bone Res. 2025;13(1):75.
30.
ManoleENiculiteCLambrescuIM, et al. Macrophages and stem cells: two to tango for tissue repair?Biomolecules. 2021;11(5):697.
31.
OhJHKimDHJeongHJParkJHRheeSM.Effect of recombinant human parathyroid hormone on rotator cuff healing after arthroscopic repair. Arthroscopy. 2019;35(4):1064-1071.
32.
PiitulainenKYlinenJKautiainenHHäkkinenA.The relationship between functional disability and health-related quality of life in patients with a rotator cuff tear. Disabil Rehabil. 2012;34(24):2071-2075.
33.
RomacJMShahidRASwainSMVignaSRLiddleRA.Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis. Nat Commun. 2018;9(1):1715.
34.
SchandaJEKeiblCHeimelP, et al. Zoledronic acid substantially improves bone microarchitecture and biomechanical properties after rotator cuff repair in a rodent chronic defect model. Am J Sports Med. 2020;48(9):2151-2160.
35.
ShahSAKormpakisIHavliogluN, et al. Sclerostin antibody treatment enhances rotator cuff tendon-to-bone healing in an animal model. J Bone Joint Surg Am. 2017;99(10):855-864.
36.
ShahSAKormpakisIHavliogluN, et al. Sclerostin antibody treatment enhances tendon-to-bone healing in a rotator cuff animal model. J Orthop Res. 2017;35.
37.
ShaneEBurrDAbrahamsenB, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29(1):1-23.
38.
SilvaMJRittyTMDitsiosK, et al. Tendon injury response: assessment of biomechanical properties, tissue morphology and viability following flexor digitorum profundus tendon transection. J Orthop Res. 2004;22(5):990-997.
39.
SunYKwakJMKholinneE, et al. Nonabsorbable suture knot on the tendon affects rotator cuff healing: a comparative study of the knots on tendon and bone in a rat model of rotator cuff tear. Am J Sports Med. 2019;47(12):2809-2815.
40.
SyedaRXuJDubinAE, et al. Chemical activation of the mechanotransduction channel Piezo1. Elife. 2015;4:e07369.
41.
TanakaKKanazawaTGotohM, et al. Effects of estrogen-deficient state on rotator cuff healing. Am J Sports Med. 2019;47(2):389-397.
42.
TangZWeiXLiT, et al. Three-dimensionally printed Ti2448 with low stiffness enhanced angiogenesis and osteogenesis by regulating macrophage polarization via Piezo1/YAP signaling axis. Front Cell Dev Biol. 2021;9:750948.
43.
XiaoB.Mechanisms of mechanotransduction and physiological roles of PIEZO channels. Nat Rev Mol Cell Biol. 2024;25(11):886-903.
44.
XieDSunYLiuZ, et al. Antiosteoporotic treatment promotes tendon-to-bone healing after rotator cuff repair: a systematic review of animal studies. Bone Joint Res. 2026;15(2):157-166.
45.
XuJSuWChenJ, et al. The effect of antiosteoporosis therapy with risedronate on rotator cuff healing in an osteoporotic rat model. Am J Sports Med. 2021;49(8):2074-2084.
46.
XuJYeZChenC, et al. Abaloparatide improves rotator cuff healing via anabolic effects on bone remodeling in a chronic rotator cuff tear model of rat with osteoporosis: a comparison with denosumab. Am J Sports Med. 2022;50(6):1550-1563.
47.
XuLLiTCaoY, et al. PIEZO1 mediates periostin+ myofibroblast activation and pulmonary fibrosis in mice. J Clin Invest. 2025;135(11):e184158.
48.
YakackiCMPoukalovaMGuldbergRE, et al. The effect of the trabecular microstructure on the pullout strength of suture anchors. J Biomech. 2010;43(10):1953-1959.
49.
YangXLinCChenX, et al. Structure deformation and curvature sensing of PIEZO1 in lipid membranes. Nature. 2022;604(7905):377-383.
50.
YonemitsuRTokunagaTShukunamiC, et al. Fibroblast growth factor 2 enhances tendon-to-bone healing in a rat rotator cuff repair of chronic tears. Am J Sports Med. 2019;47(7):1701-1712.
51.
YoonJPChungSWJungJW, et al. Is a local administration of parathyroid hormone effective to tendon-to-bone healing in a rat rotator cuff repair model?J Orthop Res. 2020;38(1):82-91.
52.
ZhaoSPengLXieG, et al. Effect of the interposition of calcium phosphate materials on tendon-bone healing during repair of chronic rotator cuff tear. Am J Sports Med. 2014;42(8):1920-1929.
ZhaoYShangDZhangY, et al. The effectiveness of intravenous zoledronic acid in elderly patients with osteoporosis after rotator cuff repair: a retrospective study. Sci Rep. 2024;14(1):20891.
55.
ZhuMLin TayMLimKS, et al. Novel growth factor combination for improving rotator cuff repair: a rat in vivo study. Am J Sports Med. 2022;50(4):1044-1053.
56.
ZubairKYouCKwonGKangK.Two faces of macrophages: training and tolerance. Biomedicines. 2021;9(11):1596.
