Skeletal interoception regulates joint homeostasis and PGE2-induced pain: implication of disease-modifying treatment

Abstract

Interoception is a core process through which the body perceives its internal state and regulates physiological homeostasis via bidirectional communication between the central and peripheral nervous system. Skeletal interoception is a specific circuitry for the brain control of the weight-bearing system, particularly responsible for sensing bone-derived internal signals to maintain skeletal homeostasis in response to mechanical loading. Recent studies uncovered that prostaglandin E2 (PGE2) plays a crucial role in skeletal interoception, and is therefore involved in major skeletal disorders and pain conditions such as low back pain, osteoarthritis and particularly ankle osteoarthritis (AOA). Ankle pain is clinically common, with a prevalence of 9%-15% among adults, severely impairing work productivity and quality of life. This article reviews the progress of skeletal interoception in skeletal pathogenesis and pain, with AOA as an example. Specifically, it discusses PGE2 and skeletal interoception in relation to pain and inflammation. We also attempted to interpret non-steroidal anti-inflammatory drugs (NSAIDs), surgical interventions and Traditional Chinese Medicine (TCM) therapies, especially acupuncture and electroacupuncture, in the therapy of pain and osteoarthritis from the viewpoint of skeletal interoception. Interoception is an emerging science in understanding how the brain regulates peripheral organs. Skeletal interoception mediated by PGE2 provides an opportunity to understand the potential of NSAIDs and acupuncture in regulating interoception for the treatment of skeletal disorders including ankle pain.

References

[1] Laura C, Henrik HH. The role of the skin in interoception: a neglected organ?. Psychol. Sci., 2023, 18: 224-238

[2] Parma C, et al.. An overview of the bodily awareness representation and interoception: insights and progress in the field of neurorehabilitation research. Brain Sci., 2024, 14: 386

[3] Quadt L, Critchley HD, Garfinkel SN. The neurobiology of interoception in health and disease. Ann. N. Y. Acad. Sci., 2018, 1428: 112-128

[4] Nooij J, Zampieri N. The making of a proprioceptor: a tale of two identities. Trends Neurosci., 2023, 46: 1083-1094

[5] Ma Q. A functional subdivision within the somatosensory system and its implications for pain research. Neuron, 2022, 110: 749-769

[6] Dunn W, et al.. Measuring change in somatosensation across the lifespan. Am. J. Occup. Ther., 2015, 69: 6903290020p1-6903290020p9

[7] Wallman-Jones A, Perakakis P, Tsakiris M, Schmidt M. Physical activity and interoceptive processing: theoretical considerations for future research. Int. J. Psychophysiol., 2021, 166: 38-49

[8] Xiao Y, et al.. Interoceptive regulation of skeletal tissue homeostasis and repair. Bone Res, 2023, 11: 48

[9] Lv X, Gao F, Cao X. Skeletal interoception in bone homeostasis and pain. Cell Metab., 2022, 34: 1914-1931

[10] Zhu H, et al.. Targeting skeletal interoception: a novel mechanistic insight into intervertebral disc degeneration and pain management. J. Orthop. Surg. Res., 2025, 20: 159

[11] Yang D, Xu J, Xu K, Xu P. Skeletal interoception in osteoarthritis. Bone Res, 2024, 12: 22

[12] Bai L, et al.. Skeletal interoception and prospective application in biomaterials for bone regeneration. Bone Res., 2025, 13: 1

[13] Yu J, et al.. Bone-brain interaction: mechanisms and potential intervention strategies of biomaterials. Bone Res., 2025, 13: 38

[14] Xu Z, et al.. Interoceptive regulation of bone homeostasis: the interplay between the nervous and skeletal systems in pathophysiology. Pharmacol. Res., 2025, 218 ArticleID: 107850

[15] Yang D, et al.. The organ-joint axes in osteoarthritis: significant pathogenesis and therapeutic targets. Aging Dis., 2024, 16: 2999-3021

[16] Gao F, et al.. Brain regulates weight bearing bone through PGE2 skeletal interoception: implication of ankle osteoarthritis and pain. Bone Res., 2024, 12: 16

[17] Guo Q, et al.. Unloading-induced skeletal interoception alters hypothalamic signaling to promote bone loss and fat metabolism. Adv. Sci., 2023, 10 ArticleID: e2305042

[18] Jiang W, et al.. PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis. Bone Res., 2022, 10: 27

[19] Sun Q, et al.. Inhibition of PGE2 in subchondral bone attenuates osteoarthritis. Cells, 2022, 11: 2760

[20] Chen H, et al.. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat. Commun., 2019, 10 ArticleID: 181

[21] Zhen G, et al.. Mechanical stress determines the configuration of TGFβ activation in articular cartilage. Nat. Commun., 2021, 12 ArticleID: 1706

[22] Wang Z, et al.. Hypothalamus regulates anabolic metabolism of articular cartilage superficial chondrocytes through PGE2 skeletal interoception. Adv. Sci., 2025, 12 ArticleID: e2501039

[23] Xia Z. Skeletal interoception: an emerging area for musculoskeletal research. Biomater. Transl., 2022, 3: 237-239

[24] Xue P, et al.. PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxib. Bone Res., 2021, 9: 36

[25] Zhu J, et al.. Aberrant subchondral osteoblastic metabolism modifies NaV1.8 for osteoarthritis. eLife, 2020, 9 ArticleID: e57656

[26] Pilbeam C. Prostaglandins and bone. Handb. Exp. Pharmacol., 2020, 262: 157-175

[27] Chen RP, et al.. Progress in diagnosis and treatment of acute injury to the anterior talofibular ligament. World J. Clin. Cases, 2023, 11: 3395-3407

[28] Zhang Y, Wu W, Chen Z. Dual roles of prostaglandin E2 (PGE2) in bone remodeling and pain management: bridging the gap in osteoarthritis research. Mediators Inflamm., 2025, 2025: 8882429

[29] Ohashi Y, et al.. Mechanisms of peripheral and central sensitization in osteoarthritis pain. Cureus, 2023, 15e35331

[30] Liu S, et al.. TRPV1 channel activated by the PGE2/EP4 pathway mediates spinal hypersensitivity in a mouse model of vertebral endplate degeneration. Oxid. Med. Cell. Longev., 2021, 2021 ArticleID: 9965737

[31] Ikeda-Miyagawa Y, et al.. Peripherally increased artemin is a key regulator of TRPA1/V1 expression in primary afferent neurons. Mol. Pain., 2015, 11 ArticleID: 8

[32] Zhu S, et al.. The role of glial cell line-derived neurotrophic factor family member artemin in neurological disorders and cancers. Cell Prolif., 2020, 53 ArticleID: e12860

[33] Ning Y, Xiao L. Advances in pain sensitization and pharmaceutical treatment of osteoarthritis pain. Chin. J. Painol, 2021, 17: 664-669

[34] Samuchiwal SK, Balestrieri B, Raff H, Boyce JA. Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. J. Biol. Chem., 2017, 292: 8195-8206

[35] Wang P, Zhu F, Konstantopoulos K. Prostaglandin E2 induces interleukin-6 expression in human chondrocytes via cAMP/protein kinase a- and phosphatidylinositol 3-kinase-dependent NF-κB activation. Am. J. Physiol. Cell Physiol., 2010, 298: C1445-C1456

[36] Omori K, et al.. Multiple roles of the PGE2 -EP receptor signal in vascular permeability. Br. J. Pharmacol., 2014, 171: 4879-4889

[37] Hu, R., Chen, Z., Liang, G. & Yang, Y. Potential role of the PGE2-EP4-Ca²⁺ signaling axis in post-traumatic osteoarthritis. J. Vis. Exp.222, e68602 (2025).

[38] Attur M, et al.. Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor. J. Immunol., 2008, 181: 5082-5088

[39] De Roover A, Escribano-Núñez A, Monteagudo S, Lories R. Fundamentals of osteoarthritis: inflammatory mediators in osteoarthritis. Osteoarthr. Cartil., 2023, 31: 1303-1311

[40] Wang C, et al.. Safflower yellow alleviates osteoarthritis and prevents inflammation by inhibiting PGE2 release and regulating NF-κB/SIRT1/AMPK signaling pathways. Phytomed, 2020, 78 ArticleID: 153305

[41] He M, et al.. FSGT capsule inhibits IL-1β-induced inflammation in chondrocytes and ameliorates osteoarthritis by upregulating LncRNA PACER and downregulating COX2/PGE2. Immun. Inflamm. Dis., 2024, 12 ArticleID: e1334

[42] Amodeo G, et al.. Neuroinflammation in osteoarthritis: from pain to mood disorders. Biochem. Pharmacol., 2024, 228 ArticleID: 116182

[43] Yang M, et al.. Astilbin influences the progression of osteoarthritis in rats by down-regulation of PGE-2 expression via the NF-κB pathway. Ann. Transl. Med., 2020, 8: 766

[44] Peng P, et al.. Imrecoxib attenuates osteoarthritis by modulating synovial macrophage polarization through inactivating COX-2/PGE2 signaling pathway. Front. Bioeng. Biotechnol., 2025, 13 ArticleID: 1526092

[45] Zhang C, Li X, Wen P, Li Y. Ellagic acid improves osteoarthritis by inhibiting PGE2 production in M1 macrophages via targeting PTGS2. Clin. Exp. Pharmacol. Physiol., 2024, 51 ArticleID: e13918

[46] Li X, et al.. Overall adjustment acupuncture improves osteoporosis and exerts an endocrine-modulating effect in ovariectomized rats. Front. Endocrinol., 2022, 13 ArticleID: 1074516

[47] Li X, et al.. Interventional study on acupuncture for osteoporosis induced by arcuate nucleus lesion in rats. Tianjin J. Tradit. Chin. Med., 2007, 5: 380-383

[48] Zhu Y, et al.. [electroacupuncture improves obesity and promotes white adipose tissue browning by regulating central glucagon-like peptide-1]. Acupunct. Res., 2023, 48: 727-735

[49] Wang J, et al.. Observation on the accumulative analgesic effect of electroacupuncture and the expression of protein kinase a in hypothalamus and hippocampus in chronic pain or/and ovariectomized rats. Acupunct. Res., 2008, 33: 80-87

[50] Fang J, et al.. Electroacupuncture regulates pain transition through inhibiting PKCε and TRPV1 expression in dorsal root ganglion. Front. Neurosci., 2021, 15 ArticleID: 685715

[51] Yang KW, et al.. Effects of electroacupuncture on pain behavior and pain-related factors in spinal cord dorsal horn and dorsal root ganglia of rats with knee osteoarthritis. Acupunct. Res., 2020, 45: 818-822

[52] Krause F, Anwander H. Osteochondral lesion of the talus: still a problem?. Efort Open Rev., 2022, 7: 337-343

[53] Negahban H, et al.. Comparing the effects of ankle integral and conventional physiotherapy on pain, range of motion, balance, disability, and treatment effectiveness in patients with chronic ankle instability: randomized controlled trial. Clin. Rehabil., 2023, 37: 362-372

[54] Hertel J, Corbett RO. An updated model of chronic ankle instability. J. Athl. Train., 2019, 54: 572-588

[55] Nishimura A, et al.. Prevalence and risk factors of ankle osteoarthritis in a population-based study. Foot Ankle Surg., 2024, 30: 389-393

[56] Sung SH, et al.. Clinical evidence of bee venom acupuncture for ankle pain: a review of clinical research. Toxins, 2025, 17: 257

[57] Murray C, et al.. Population prevalence and distribution of ankle pain and symptomatic radiographic ankle osteoarthritis in community dwelling older adults: a systematic review and cross-sectional study. PLOS One, 2018, 13: e0193662

[58] Urits I, et al.. Minimally invasive treatment of chronic ankle instability: a comprehensive review. Curr. Pain. Headache Rep., 2020, 24 ArticleID: 8

[59] Cotchett M, Frescos N, Whittaker GA, Bonanno DR. Psychological factors associated with foot and ankle pain: a mixed methods systematic review. J. Foot Ankle Res., 2022, 15 ArticleID: 10

[60] Altomare D, et al.. Evidence-based treatment choices for acute lateral ankle sprain: a comprehensive systematic review. Eur. Rev. Med. Pharmacol. Sci., 2022, 26: 1876-1884

[61] Vuurberg G, et al.. Diagnosis, treatment and prevention of ankle sprains: update of an evidence-based clinical guideline. Br. J. Sports Med., 2018, 52: 956

[62] Luan L, et al.. Effects of acupuncture or similar needling therapy on pain, proprioception, balance, and self-reported function in individuals with chronic ankle instability: a systematic review and meta-analysis. Complement. Ther. Med., 2023, 77 ArticleID: 102983

[63] Tejero S, et al.. Conservative treatment of ankle osteoarthritis. J. Clin. Med., 2021, 10: 4561

[64] Arnold JB, et al.. International foot and ankle osteoarthritis consortium review and research agenda for diagnosis, epidemiology, burden, outcome assessment and treatment. Osteoarthr. Cartil., 2022, 30: 945-955

[65] Bjarnason I, et al.. Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs. Gastroenterology, 2018, 154: 500-514

[66] Doña I, et al.. Progress in understanding hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. Allergy, 2020, 75: 561-575

[67] Varga Z, Sabzwari SRA, Vargova V. Cardiovascular risk of nonsteroidal anti-inflammatory drugs: an under-recognized public health issue. Cureus, 2017, 9: e1144

[68] Goldberg AJ, et al.. Total ankle replacement versus arthrodesis for end-stage ankle osteoarthritis: a randomized controlled trial. Ann. Intern. Med., 2022, 175: 1648-1657

[69] Wu Y. Surgical Treatment of Ankle Osteoarthritis. J. Clin. Orthop. Res, 2018, 3: 321-322

[70] Al-Waeli H, et al.. Non-steroidal anti-inflammatory drugs and bone healing in animal models-a systematic review and meta-analysis. Syst. Rev., 2021, 10 ArticleID: 201

[71] Marjoribanks J, Ayeleke RO, Farquhar C, Proctor M. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea. Cochrane Database Syst. Rev., 2015, 2015: CD001751

[72] Ryan PM, et al.. NSAID use in orthopedic surgery: a review of current evidence and clinical practice guidelines. J. Orthop. Res., 2024, 42: 707-716

[73] Cardenas-Estrada E, et al.. Efficacy and safety of celecoxib in the treatment of acute pain due to ankle sprain in a Latin American and Middle Eastern population. J. Int. Med. Res., 2009, 37: 1937-1951

[74] Ortiz MI, et al.. Effectiveness of diclofenac, ketorolac and etoricoxib in the treatment of acute pain from ankle fracture. Proc. West. Pharmacol. Soc., 2010, 53: 46-48

[75] Richard MJ, Driban JB, McAlindon TE. Pharmaceutical treatment of osteoarthritis. Osteoarthr. Cartil., 2023, 31: 458-466

[76] Derry S, et al.. Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database Syst. Rev., 2015, 2015: CD007402

[77] Lionberger DR, et al.. Diclofenac epolamine topical patch relieves pain associated with ankle sprain. J. Pain. Res., 2011, 4: 47-53

[78] Cai Y, et al.. Tissue levels of flurbiprofen in the rat plantar heel after short-duration topical iontophoresis are sufficient to induce pharmacodynamic responses to local pain stimuli. Pharmaceutics, 2020, 12: 608

[79] Fu W, Zhang X. Clinical efficacy of acupuncture combined with massage in the treatment of non-fracture ankle sports injuries. Res Sports Sci. Health, 2025, 4: 20-24

[80] Long X, Xie H. Research progress on the treatment of acute ankle sprains using both Chinese and Western medicine. Ginseng Res., 2023, 35: 42-45

[81] Lv Y, Duan Y. Effect of LYU Jingshan’s pair Houxi(S13)-Huantiao(GB30) on plasma IL-6,NO, and PGE2 of SD rats with lumbar interwertebral disc herniation. World J. Integr. Tradit. West Med, 2020, 15: 630-633

[82] Wu W, Li Y, Shi L. Effect of “hand-six-needle” acupuncture on range of motion and inflammatory factors in patients with scapulohumeral periarthritis. J. Clin. Acupunct. Moxibust, 2019, 35: 26-29

[83] Gan Y, Long Q, Huang C, Du Y. Research progress on the effects of acupuncture in knee osteoarthritis. Forum Tradit. Chin. Med., 2018, 33: 64-67

[84] Ma, J. Comparative Study on the Effects of Acupuncture and Moxibustion on the Expressions of IL-8, PGE2, Spinal OX-42 and BDNF in Rats with Myofascial Pain Syndrome (Liaoning University of Traditional Chinese Medicine, Shenyang, 2023).

[85] Lin JG, Kotha P, Chen YH. Understandings of acupuncture application and mechanisms. Am. J. Transl. Res., 2022, 14: 1469-1481

[86] Xu H, et al.. Clinical observation on the treatment of acute ankle sprain by acupuncture at“Tongqi Ashi Acuoint”. J. Emerg. Tradit. Chin. Med., 2023, 32: 1429-1432

[87] You Y, Yang F, Zhang Y. Effect of traditional Chinese medicine acupuncture combined with shenxiao tongluo powder on foot function and balance function for patients with chronic ankle instability. J. Sichuan Tradit. Chin. Med., 2021, 39: 192-194

[88] Deng, Z. Clinical Observation on Therapeutic Effect of Warm Acupuncture Combined with PRP on Traumatic Ankle Arthritis (Guangzhou University of Chinese Medicine, Guangzhou, 2025).

[89] Wu H. Research progress on acupuncture treatment for gouty arthritis. Guangming J. Chin. Med., 2023, 38: 4693-4696

[90] Wang G, Chen H, Zhu J, Wang W. Clinical observation on electroacupuncture combined with press tack needle in the treatment of lumbar disc herniation. Chin. J. Typ. Cases., 2025, 19: 498-501

[91] Fan Y, et al.. Study of the inhibiting effects of ear point sticking plus electroacupuncture on synovial fibrosis and endoplasmic reticulum stress in knee osteoarthritis model rats. Shanghai J. Acupunct. Moxibust., 2024, 43: 906-914

[92] Zheng L, et al.. Electroacupuncture at two points of piriform muscle for lumbar disc herniation in model rats. World Chin. Med., 2023, 18: 792-795

[93] Deng, H. Clinical Efficacy of Electroacupuncture Treatment for Ankle Sprains Based on Ultrasound Elastography Observation (Nanjing University of Chinese Medicine, Nanjing, 2025).

[94] Liu Z. Efficacy of electroacupuncture for chronic ankle instability based on Hiller classification model. Chin. Acupunct. Moxibust., 2023, 43: 561-564

[95] Zhong J, et al.. Effects of babu ointment for clearing heat and removing blood stasis and babu ointment clearing heat and invigorating Qi and removing blood stasis on PGE2 in model of acute soft tissue injury in rabbits. Chin. Arch. Tradit. Chin. Med., 2023, 41: 187-190

[96] Jiang S, et al.. Effect of heat of blood and invigorate Qi, clear heat and remove blood stasis chinese medicine on experimental animal PGE2. Chin. Foreign Med. Treat., 2019, 38: 4-6

[97] Li J, Zhang H. Effect of extracorporeal shock wave combined with traditional Chinese medicine fumigation in the treatment of spinal dorsal ramus syndrome and its influence on serum IL-6 and PGE2 levels. Clin. Res. Pract., 2021, 6: 135-137

[98] Yan, W. Effect of Huayu Qushi Decoction on the Expression of Pain Factors in Peripheral Blood of Patients with Early And Middle Stage KOA and Evaluation of Its Therapeutic Efficacy (Guangxi University of Chinese Medicine, Nanning, 2024).

[99] Zhang L, et al.. Effect of ulnar tibia needling combined with the electro-axupuncture therapy and fumigation on lumbar disc herniation and its influence on the level of prostaglandin E2 and the life quality. Jilin J. Chin. Med., 2022, 42: 1345-1349

[100] Maffulli N, et al.. Outcome of ankle arthrodesis and ankle prosthesis: a review of the current status. Br. Med. Bull., 2017, 124: 91-112

[101] Xu X, Wu Y. Research progress of total ankle arthroplasty. Chin. J. Bone Jt. Surg., 2023, 16: 750-755

[102] Balaji SM, Selvaraj V, Devadoss S, Devadoss A. Transfibular ankle arthrodesis: a novel method for ankle fusion - a short term retrospective study. Indian J. Orthop., 2017, 51: 75-80

[103] DeHeer PA, Catoire SM, Taulman J, Borer B. Ankle arthrodesis: a literature review. Clin. Podiatr. Med. Surg., 2012, 29: 509-527

[104] Faber FWM, et al.. Outcome after 52 salto ankle prostheses implanted by a single surgeon. Adv. Orthop., 2018, 2018 ArticleID: 2735634

[105] Xi S, Kang X. Effects of ankle fusion surgery with anterior and lateral locking plate internal fixation on ankle function, IL-1β and IGF-1 levels in patients with post-traumatic ankle osteoarthritis. Clin. Res. Pract., 2022, 7: 74-77

[106] Jeyaseelan L, et al.. Outcomes following total ankle arthroplasty: a review of the registry data and current literature. Orthop. Clin. North Am., 2019, 50: 539-548

[107] Loveday DT, et al.. The 15 year ankle arthroplasty experience in a university hospital. Foot Ankle Surg., 2022, 28: 217-221

[108] Tang TH, et al.. The efficacy of ankle arthroplasty on motor function recovery in patients with orthopedic ankle injury: a systematic review and meta-analysis. Ann. Palliat. Med., 2022, 11: 621-630

[109] Shaffrey I, Henry J, Demetracopoulos C. An evaluation of the total ankle replacement in the modern era: a narrative review. Ann. Transl. Med., 2024, 12: 71

[110] Almutairi T, et al.. Safety and efficacy of total ankle arthroplasty versus ankle arthrodesis for ankle osteoarthritis: a systematic review and meta-analysis. Foot, 2023, 55 ArticleID: 101980

[111] Liu W, Guo NY, Wang JQ, Bing Bing X. Osteoarthritis: mechanisms and therapeutic advances. MedComm, 2025, 6 ArticleID: e70290

[112] Allegri M, et al.. Mechanisms of low back pain: a guide for diagnosis and therapy. F1000Research, 2016, 5: 1530

[113] Tedeschi R, Giorgi F, Platano D, Berti L. Classifying low back pain through pain mechanisms: a scoping review for physiotherapy practice. J. Clin. Med., 2025, 14: 412

[114] Hauser RA, et al.. Lumbar instability as an etiology of low back pain and its treatment by prolotherapy: a review. J. Back Musculoskelet. Rehabil., 2022, 35: 701-712

[115] Ni S, et al.. Sensory innervation in porous endplates by netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice. Nat. Commun., 2019, 10 ArticleID: 5643

[116] Zhang M, et al.. Loss of the PGE2 receptor EP1 enhances bone acquisition, which protects against age and ovariectomy-induced impairments in bone strength. Bone, 2015, 72: 92-100

[117] Słupski W, Jawień P, Paulina B. Botanicals in postmenopausal osteoporosis. Nutrients, 2021, 13: 1609

[118] Yoshida K, et al.. Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proc. Natl. Acad. Sci. USA., 2002, 99: 4580-4585

[119] Samuels JS, et al.. Prostaglandin E2 and IL-23 interconnects STAT3 and RoRγ pathways to initiate Th17 CD4+ T-cell development during rheumatoid arthritis. Inflamm. Res., 2018, 67: 589-596

[120] Jang S, Sunhee EJ, Lee JJ. Rheumatoid arthritis: pathogenic roles of diverse immune cells. Int. J. Mol. Sci., 2022, 23: 905

[121] Du B, et al.. The prostaglandin E2 increases the production of IL-17 and the expression of costimulatory molecules on γδ T cells in rheumatoid arthritis. Scand. J. Immunol., 2020, 91 ArticleID: e12872

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