# Macrophage polarisation under immune regulation as a therapeutic target for tendon-bone healing: multifactorial regulation and mechanistic insights

**Authors:** Wanxue Wang, Liang Zhang, Yu Jiang, Dexi Cui, Kehao Hou, Shengquan Ren, Xia Zhao, Yingze Zhang, Ning Yu, Chao Qi, Kuishuai Xu

PMC · DOI: 10.3389/fimmu.2026.1737444 · 2026-02-03

## TL;DR

This paper explores how guiding macrophage polarization, especially to the anti-inflammatory M2 type, can improve healing at the tendon-bone interface.

## Contribution

The paper provides mechanistic insights into how biomaterials can modulate macrophage polarization to enhance tendon-bone healing.

## Key findings

- M2 macrophage polarization is crucial for long-term tendon-bone healing.
- Biomaterials can influence macrophage behavior through multiple signaling pathways.
- Controlling macrophage polarization offers new strategies for developing healing-promoting biomaterials.

## Abstract

Recovery from a variety of surgical treatments, including arthroscopic rotator cuff repair and anterior cruciate ligament restoration, depends heavily on tendon-bone healing. There is mounting evidence that the polarisation of macrophages, namely M2 polarisation, is a crucial regulating factor in the repair of tendon-bone. Early tendon-bone repair is greatly aided by M1 macrophages, which have a pro-inflammatory nature. Long-term pro-inflammatory activity, however, seriously hinders the healing process. Therefore, one of the most important challenges in tendon-bone healing is to guide macrophages into the anti-inflammatory M2 phenotype. The effect of macrophage polarisation on tendon-bone healing is thoroughly investigated in this paper, along with methods for modifying macrophage polarisation. Importantly, it demonstrates how biomaterials control this process via a variety of signalling channels, providing fresh ideas for creating cutting-edge biomaterials (such as scaffolds, hydrogels, exosomes, etc.) that encourage tendon-bone mending by focusing on immune responses from macrophages.

## Full-text entities

- **Genes:** TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, TRPM7 (transient receptor potential cation channel subfamily M member 7) [NCBI Gene 54822] {aka ALSPDC, CHAK, CHAK1, LTRPC7, LTrpC-7, TRP-PLIK}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, JAK3 (Janus kinase 3) [NCBI Gene 3718] {aka JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, KDR (kinase insert domain receptor) [NCBI Gene 3791] {aka CD309, FLK1, VEGFR, VEGFR2}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, PPP1R12A (protein phosphatase 1 regulatory subunit 12A) [NCBI Gene 4659] {aka GUBS, M130, MBS, MYPT1}, PIEZO1 (piezo type mechanosensitive ion channel component 1 (Er blood group)) [NCBI Gene 9780] {aka DHS, ER, FAM38A, LMPH3, LMPHM6, Mib}, CCR7 (C-C motif chemokine receptor 7) [NCBI Gene 1236] {aka BLR2, CC-CKR-7, CCR-7, CD197, CDw197, CMKBR7}, OSM (oncostatin M) [NCBI Gene 5008], CD163 (CD163 molecule) [NCBI Gene 9332] {aka M130, MM130, SCARI1}, SPP1 (secreted phosphoprotein 1) [NCBI Gene 6696] {aka BNSP, BSPI, ETA-1, OPN}, WNT3A (Wnt family member 3A) [NCBI Gene 89780], Calb2 (calbindin 2) [NCBI Gene 117059], IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, DVL1P1 (dishevelled segment polarity protein 1 pseudogene 1) [NCBI Gene 8215] {aka DVL-22, DVL1L1}, IGF1 (insulin like growth factor 1) [NCBI Gene 3479] {aka IGF, IGF-I, IGFI, MGF}, CXCR3 (C-X-C motif chemokine receptor 3) [NCBI Gene 2833] {aka CD182, CD183, CKR-L2, CMKAR3, GPR9, IP10-R}, Acta2 (actin alpha 2, smooth muscle, aorta) [NCBI Gene 11475] {aka 0610041G09Rik, Actvs, SMAalpha, SMalphaA, a-SMA, alphaSMA}, STAT6 (signal transducer and activator of transcription 6) [NCBI Gene 6778] {aka D12S1644, HIES6, IL-4-STAT, STAT6B, STAT6C}, APC (APC regulator of Wnt signaling pathway) [NCBI Gene 324] {aka BTPS2, DESMD, DP2, DP2.5, DP3, GS}, OSMR (oncostatin M receptor) [NCBI Gene 9180] {aka IL-31R-beta, IL-31RB, OSMRB, OSMRbeta, PLCA1}, TAFAZZIN (tafazzin, phospholipid-lysophospholipid transacylase) [NCBI Gene 6901] {aka BTHS, CMD3A, EFE, EFE2, G4.5, LVNCX}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, PLXNB1 (plexin B1) [NCBI Gene 5364] {aka PLEXIN-B1, PLXN5, SEP}, ANXA1 (annexin A1) [NCBI Gene 301] {aka ANX1, LPC1}, PLXND1 (plexin D1) [NCBI Gene 23129] {aka CHTD9, PLEXD1}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, BMP2 (bone morphogenetic protein 2) [NCBI Gene 650] {aka BDA2, BMP2A, SSFSC, SSFSC1}, Mrc1 (mannose receptor, C type 1) [NCBI Gene 17533] {aka CD206, MR}, IRF1 (interferon regulatory factor 1) [NCBI Gene 3659] {aka IMD117, IRF-1, MAR}, IL12B (interleukin 12B) [NCBI Gene 3593] {aka CLMF, CLMF2, IL-12B, IMD28, IMD29, NKSF}, Pf4 (platelet factor 4) [NCBI Gene 360918] {aka Cxcl4, PF-4, Pf4a, RATPF4A}, BMPR1B (bone morphogenetic protein receptor type 1B) [NCBI Gene 658] {aka ALK-6, ALK6, AMD3, AMDD, BDA1D, BDA2}, TNFRSF11B (TNF receptor superfamily member 11b) [NCBI Gene 4982] {aka OCIF, OPG, PDB5, TR1}, ARG1 (arginase 1) [NCBI Gene 383], PDCD4 (programmed cell death 4) [NCBI Gene 27250] {aka H731}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, Gsdmd (gasdermin D) [NCBI Gene 69146] {aka 1810036L03Rik, DF5L, Dfna5l, GsdmD-1, Gsdmdc1, M2-4}, MAF (MAF bZIP transcription factor) [NCBI Gene 4094] {aka AYGRP, CCA4, CTRCT21, c-MAF}, RHOA (ras homolog family member A) [NCBI Gene 387] {aka ARH12, ARHA, EDFAOB, RHO12, RHOH12}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, IRF4 (interferon regulatory factor 4) [NCBI Gene 3662] {aka IMD131, LSIRF, MUM1, NF-EM5, SHEP8}, CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, CXCL9 (C-X-C motif chemokine ligand 9) [NCBI Gene 4283] {aka CMK, Humig, MIG, SCYB9, crg-10}, HNF4A (hepatocyte nuclear factor 4 alpha) [NCBI Gene 3172] {aka FRTS4, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha}, YAP1 (Yes1 associated transcriptional regulator) [NCBI Gene 10413] {aka COB1, YAP, YAP-1, YAP2, YAP65, YKI}, IL6ST (interleukin 6 cytokine family signal transducer) [NCBI Gene 3572] {aka CD130, CDW130, GP130, HIES4, HIES4A, HIES4B}, RUNX2 (RUNX family transcription factor 2) [NCBI Gene 860] {aka AML3, CBF-alpha-1, CBFA1, CCD, CCD1, CLCD}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, ITGAV (integrin subunit alpha V) [NCBI Gene 3685] {aka CD51, IDNDC, MSK8, VNRA, VTNR}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, GDF7 (growth differentiation factor 7) [NCBI Gene 151449] {aka BMP12}, Adgre1 (adhesion G protein-coupled receptor E1) [NCBI Gene 13733] {aka DD7A5-7, EGF-TM7, Emr1, F4/80, Gpf480, Ly71}, MFGE8 (milk fat globule EGF and factor V/VIII domain containing) [NCBI Gene 4240] {aka BA46, EDIL1, HMFG, HsT19888, MFG-E8, MFGM}, CXCL10 (C-X-C motif chemokine ligand 10) [NCBI Gene 3627] {aka C7, IFI10, INP10, IP-10, SCYB10, crg-2}
- **Diseases:** alcohol abuse (MESH:D000437), mitochondrial dysfunction (MESH:D028361), pain (MESH:D010146), bone tumour (MESH:D001859), fibrosis (MESH:D005355), injury (MESH:D014947), inflammation (MESH:D007249), anterior cruciate ligament (MESH:D000070598), traumatic brain injury (MESH:D000070642), rupture (MESH:D012421), diabetes (MESH:D003920), cancer (MESH:D009369), sports injury (MESH:D001265), hypoxic (MESH:D002534), tear (MESH:D012167), hypoxia (MESH:D000860), opioid (MESH:D009293), OA (MESH:D010003), Achilles tendon avulsion injuries (MESH:D013708), TBI (MESH:D052256), macrophage deficiency (MESH:D055501), knee osteoarthritis (MESH:D020370), bone defect (MESH:D001847), infected (MESH:D007239), African trypanosomiasis (MESH:D014353), neuropathic (MESH:D009437), rotator cuff (MESH:D000070636), breast and prostate cancer (MESH:D001943), chronic pain (MESH:D059350), musculoskeletal injuries (MESH:D009140), necrotic (MESH:D009336), atopic dermatitis (MESH:D003876)
- **Chemicals:** oxygen (MESH:D010100), sodium alginate (MESH:D000464), ammonium fluoride (MESH:C024822), Prussian blue (MESH:C000170), Chitosan (MESH:D048271), TEOS (MESH:C040733), metal (MESH:D008670), polymers (MESH:D011108), HOCl (MESH:D006997), MOFs (MESH:C040750), TAM (MESH:D013629), MOF (MESH:D000073396), PGE2 (MESH:D015232), Li (MESH:D008094), Schiff base (MESH:D012545), hydroxyl radical (MESH:D017665), cAMP (MESH:D000242), hyaluronic acid (MESH:D006820), Copper (MESH:D003300), Ag (MESH:D012834), Rosiglitazone (MESH:D000077154), SiO2 (MESH:D012822), potassium (MESH:D011188), DSF (MESH:D004221), superoxide (MESH:D013481), Si (MESH:D012825), Ca2+ (-), H2O2 (MESH:D006861), Arg (MESH:D001120), PCL (MESH:C016240), quinolone (MESH:D015363), hydroxyapatite (MESH:D017886), PLA (MESH:C033616), LPS (MESH:D008070), lipid (MESH:D008055), GSH (MESH:D005978), TiO2 (MESH:C009495), IR820 (MESH:C541053), octadecylamine (MESH:C009317), CS (MESH:D002586), SB431542 (MESH:C459179), ATP (MESH:D000255), SHP099 (MESH:C000609471), Sr (MESH:D013324), Baicalin (MESH:C038044), Ca (MESH:D002118), BBR (MESH:D001599), FA (MESH:D005492), PHBV (MESH:C052620), ROS (MESH:D017382), R848 (MESH:C402365), glucose (MESH:D005947), budesonide (MESH:D019819), Magnesium (MESH:D008274), MXene (MESH:C000723374), PLGA (MESH:D000077182), Suramin (MESH:D013498)
- **Species:** Scutellaria baicalensis (Baikal skullcap, species) [taxon 65409], Mus musculus (house mouse, species) [taxon 10090], Ovis aries (domestic sheep, species) [taxon 9940], Mphi [taxon 1847729], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116]
- **Cell lines:** RAW264.7 — Mus musculus (Mouse), Mouse leukemia, Cancer cell line (CVCL_0493), fibroblasts — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0594)

## Figures

3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12909223/full.md

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Source: https://tomesphere.com/paper/PMC12909223