Mechanisms of bone pain: Progress in research from bench to bedside

Abstract

The field of research on pain originating from various bone diseases is expanding rapidly, with new mechanisms and targets asserting both peripheral and central sites of action. The scope of research is broadening from bone biology to neuroscience, neuroendocrinology, and immunology. In particular, the roles of primary sensory neurons and non-neuronal cells in the peripheral tissues as important targets for bone pain treatment are under extensive investigation in both pre-clinical and clinical settings. An understanding of the peripheral mechanisms underlying pain conditions associated with various bone diseases will aid in the appropriate application and development of optimal strategies for not only managing bone pain symptoms but also improving bone repairing and remodeling, which potentially cures the underlying etiology for long-term functional recovery. In this review, we focus on advances in important preclinical studies of significant bone pain conditions in the past 5 years that indicated new peripheral neuronal and non-neuronal mechanisms, novel targets for potential clinical interventions, and future directions of research.

References

[1] Oostinga D, Steverink JG, van Wijck AJM, Verlaan JJ. An understanding of bone pain: A narrative review. Bone, 2020, 134: 115272

[2] Mantyh PW. Mechanisms that drive bone pain across the lifespan. Br. J. Clin. Pharm., 2019, 85: 1103-1113

[3] Havelin J, King T. Mechanisms underlying bone and joint pain. Curr. Osteoporos. Rep., 2018, 16: 763-771

[4] Rome S, Noonan K, Bertolotti P, Tariman JD, Miceli T. Bone health, pain, and mobility: Evidence-based recommendations for patients with multiple myeloma. Clin. J. Oncol. Nurs., 2017, 21: 47-59

[5] Frost C, Hansen RR, Heegaard AM. Bone pain: Current and future treatments. Br. J. Clin. Pharm., 2016, 28: 31-37

[6] Stein C. New concepts in opioid analgesia. Expert Opin. Investig. Drugs, 2018, 27: 765-775

[7] Bennett M, Paice JA, Wallace M. Pain and opioids in cancer care: Benefits, risks, and alternatives. Am. Soc. Clin. Oncol. Educ. Book, 2017, 37: 705-713

[8] Colloca L et al. Neuropathic pain. Nat. Rev. Dis. Prim., 2017, 3: 17002

[9] Schug SA, Chandrasena C. Pain management of the cancer patient. Expert Opin. Pharmacother., 2015, 16: 5-15

[10] Read SJ, Dray A. Osteoarthritic pain: A review of current, theoretical and emerging therapeutics. Expert Opin. Investig. Drugs, 2008, 17: 619-640

[11] Kanis JA. Bone and cancer: Pathophysiology and treatment of metastases. Bone, 1995, 17: 101s-105s

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

[13] Zhu S et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J. Clin. Invest., 2019, 129: 1076-1093

[14] Salaffi F, Ciapetti A, Carotti M. The sources of pain in osteoarthritis: A pathophysiological review. Reumatismo, 2014, 66: 57-71

[15] Parfitt AM. Targeted and nontargeted bone remodeling: Relationship to basic multicellular unit origination and progression. Bone, 2002, 30: 5-7

[16] Tang Y et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med., 2009, 15: 757-765

[17] Crane JL, Cao X. Function of matrix IGF-1 in coupling bone resorption and formation. J. Mol. Med (Berl.), 2014, 92: 107-115

[18] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature, 2003, 423: 337-342

[19] Suda T et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev., 1999, 20: 345-357

[20] Simonet WS et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell, 1997, 89: 309-319

[21] Ikebuchi Y et al. Coupling of bone resorption and formation by RANKL reverse signalling. Nature, 2018, 561: 195-200

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

[23] Ducy P et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell, 2000, 100: 197-207

[24] Takeda S et al. Leptin regulates bone formation via the sympathetic nervous system. Cell, 2002, 111: 305-317

[25] Elefteriou F. Impact of the autonomic nervous system on the skeleton. Physiol. Rev., 2018, 98: 1083-1112

[26] Ma Y et al. beta2-Adrenergic receptor signaling in osteoblasts contributes to the catabolic effect of glucocorticoids on bone. Endocrinology, 2011, 152: 1412-1422

[27] Kondo H et al. Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss via sympathetic nervous system. J. Biol. Chem., 2005, 280: 30192-30200

[28] Bajayo A et al. Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc. Natl. Acad. Sci. USA, 2012, 109: 15455-15460

[29] Shi Y et al. Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. Cell Metab., 2010, 11: 231-238

[30] Fukuda T et al. Sema3A regulates bone-mass accrual through sensory innervations. Nature, 2013, 497: 490-493

[31] Hayashi M et al. Osteoprotection by semaphorin 3A. Nature, 2012, 485: 69-74

[32] Nagae M et al. Osteoclasts play a part in pain due to the inflammation adjacent to bone. Bone, 2006, 39: 1107-1115

[33] Kanaya K et al. Acid-sensing ion channel 3 or P2X2/3 is involved in the pain-like behavior under a high bone turnover state in ovariectomized mice. J. Orthop. Res., 2016, 34: 566-573

[34] Epsley S et al. The Effect of inflammation on Bone. Front. Physiol., 2020, 11: 511799

[35] Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J. Clin. Invest., 2006, 116: 1186-1194

[36] Yin JJ, Pollock CB, Kelly K. Mechanisms of cancer metastasis to the bone. Cell Res., 2005, 15: 57-62

[37] Xie H et al. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat. Med., 2014, 20: 1270-1278

[38] Su W et al. Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development. JCI Insight, 2020, 5: e135446

[39] Weddell G. Axonal regeneration in cutaneous nerve plexuses. J. Anat., 1942, 77: 49-62 43

[40] Hobson MI. Increased vascularisation enhances axonal regeneration within an acellular nerve conduit. Ann. R. Coll. Surg. Engl., 2002, 84: 47-53

[41] Brain SD, Williams TJ. Substance P regulates the vasodilator activity of calcitonin gene-related peptide. Nature, 1988, 335: 73-75

[42] Leitao L et al. Osteoblasts are inherently programmed to repel sensory innervation. Bone Res., 2020, 8: 20

[43] Jung K et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int. J. Cancer, 2004, 111: 783-791

[44] Kwan Tat S et al. The differential expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in human osteoarthritic subchondral bone osteoblasts is an indicator of the metabolic state of these disease cells. Clin. Exp. Rheumatol., 2008, 26: 295-304

[45] Stapledon CJM et al. Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulphate Sodium (PPS) and implications for pain associated with knee osteoarthritis. PLoS One, 2019, 14: e0222602

[46] Han L et al. A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci., 2013, 16: 174-182

[47] Devor M. Unexplained peculiarities of the dorsal root ganglion. Pain, 1999, 6: S27-S35

[48] Wood JN et al. Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J. Neurosci., 1988, 8: 3208-3220

[49] Renthal W et al. Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury. Neuron, 2020, 108: 128-144.e9

[50] Hu G et al. Single-cell RNA-seq reveals distinct injury responses in different types of DRG sensory neurons. eNeuro, 2016, 6: 31851

[51] Rau KK et al. Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors. J. Neurosci., 2009, 29: 8612-8619

[52] Dussor G, Zylka MJ, Anderson DJ, McCleskey EW. Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors. J. Neurophysiol., 2008, 99: 1581-1589

[53] Zylka MJ. Nonpeptidergic circuits feel your pain. Neuron, 2005, 47: 771-772

[54] Cavanaugh DJ et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl. Acad. Sci. USA., 2009, 106: 9075-9080

[55] Wang H, Zylka MJ. Mrgprd-expressing polymodal nociceptive neurons innervate most known classes of substantia gelatinosa neurons. J. Neurosci., 2009, 29: 13202-13209

[56] Scholz J, Woolf CJ. Can we conquer pain? Nat. Neurosci., 2002, 5: 1062-1067

[57] Braz JM, Nassar MA, Wood JN, Basbaum AI. Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor. Neuron, 2005, 47: 787-793

[58] Block BM, Hurley RW, Raja SN. Mechanism-based therapies for pain. Drug N. Perspect., 2004, 17: 172-186

[59] Melzack R, Coderre TJ, Katz J, Vaccarino AL. Central neuroplasticity and pathological pain. Ann. N. Y. Acad. Sci., 2001, 933: 157-174

[60] Fields HL. Pain modulation: Expectation, opioid analgesia and virtual pain. Prog. Brain Res., 2000, 122: 245-253

[61] Jimenez-Andrade JM et al. A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus skin: Therapeutic opportunity for treating skeletal pain. Bone, 2010, 46: 306-313

[62] Guedon JM et al. Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain. Pain, 2016, 157: 1239-1247

[63] Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL. Nerves in bone: Evolving concepts in pain and anabolism. J. Bone Min. Res., 2019, 34: 1393-1406

[64] Mantyh P. Bone cancer pain: Causes, consequences, and therapeutic opportunities. Pain, 2013, 154 Suppl 1 S54-S62

[65] Zylka MJ, Rice FL, Anderson DJ. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron, 2005, 45: 17-25

[66] Mantyh PW. The neurobiology of skeletal pain. Eur. J. Neurosci., 2014, 39: 508-519

[67] Castaneda-Corral G et al. The majority of myelinated and unmyelinated sensory nerve fibers that innervate bone express the tropomyosin receptor kinase A. Neuroscience, 2011, 178: 196-207

[68] Aso K et al. Nociceptive phenotype of dorsal root ganglia neurons innervating the subchondral bone in rat knee joints. Eur. J. Pain., 2014, 18: 174-181

[69] Eitner A, Hofmann GO, Schaible HG. Mechanisms of osteoarthritic pain. Studies in humans and experimental models. Front. Mol. Neurosci., 2017, 10: 349

[70] Nencini S, Ivanusic JJ. The physiology of bone pain. How much do we really know? Front. Physiol., 2016, 7: 157

[71] Nencini S et al. Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain. Mol. Pain., 2017, 13

[72] Ivanusic JJ. Molecular mechanisms that contribute to bone marrow pain. Front. Neurol., 2017, 8: 458

[73] Lane NE et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N. Engl. J. Med., 2010, 363: 1521-1531

[74] Walicke PA et al. First-in-human randomized clinical trials of the safety and efficacy of tanezumab for treatment of chronic knee osteoarthritis pain or acute bunionectomy pain. Pain. Rep., 2018, 3: e653

[75] Kaan TK et al. Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain, 2010, 133: 2549-2564

[76] Mach DB et al. Origins of skeletal pain: Sensory and sympathetic innervation of the mouse femur. Neuroscience, 2002, 113: 155-166

[77] Mitchell SAT, Majuta LA, Mantyh PW. New insights in understanding and treating bone fracture pain. Curr. Osteoporos. Rep., 2018, 16: 325-332

[78] Haegerstam GA. Pathophysiology of bone pain: A review. Acta Orthop. Scand., 2001, 72: 308-317

[79] Kidd BL. Osteoarthritis and joint pain. Pain, 2006, 123: 6-9

[80] Felson DT. The sources of pain in knee osteoarthritis. Curr. Opin. Rheumatol., 2005, 17: 624-628

[81] Costa-Reis P, Sullivan KE. Chronic recurrent multifocal osteomyelitis. J. Clin. Immunol., 2013, 33: 1043-1056

[82] Kumar LD, Karthik R, Gayathri N, Sivasudha T. Advancement in contemporary diagnostic and therapeutic approaches for rheumatoid arthritis. Biomed. Pharmacother., 2016, 79: 52-61

[83] Seror P. Neuralgic amyotrophy. An update. Jt. Bone Spine, 2017, 84: 153-158

[84] Li S et al. Genotypic and phenotypic analysis in chinese cohort with autosomal recessive osteogenesis imperfecta. Front. Genet., 2020, 11: 984

[85] Zhu YF et al. Rat model of cancer-induced bone pain: Changes in nonnociceptive sensory neurons in vivo. Pain. Rep., 2017, 2: e603

[86] Milgrom DP, Lad NL, Koniaris LG, Zimmers TA. Bone pain and muscle weakness in cancer patients. Curr. Osteoporos. Rep., 2017, 15: 76-87

[87] Slosky LM, Largent-Milnes TM, Vanderah TW. Use of animal models in understanding cancer-induced bone pain. Cancer Growth Metastasis, 2015, 8: 47-62

[88] Lozano-Ondoua AN, Symons-Liguori AM, Vanderah TW. Cancer-induced bone pain: Mechanisms and models. Neurosci. Lett., 2013, 557 Pt A 52-59

[89] Zajączkowska R, Kocot-Kępska M, Leppert W, Wordliczek J. Bone pain in cancer patients: Mechanisms and current treatment. Int. J. Mol. Sci., 2019, 20: 6047

[90] Sun J et al. The endocannabinoid system: Novel targets for treating cancer induced bone pain. Biomed. Pharmacother., 2019, 120: 109504

[91] Hiraga T. Bone metastasis: Interaction between cancer cells and bone microenvironment. J. Oral. Biosci., 2019, 61: 95-98

[92] Feller L et al. Pain: Persistent postsurgery and bone cancer-related pain. J. Int. Med. Res., 2019, 47: 528-543

[93] Figura N, Smith J, Yu HM. Mechanisms of, and adjuvants for, bone pain. Hematol. Oncol. Clin. North Am., 2018, 32: 447-458

[94] Al Kaissi A et al. Musculo-skeletal abnormalities in patients with Marfan syndrome. Clin. Med Insights Arthritis Musculoskelet. Disord., 2013, 6: 1-9

[95] Bondestam J et al. Bone biopsy and densitometry findings in a child with Camurati-Engelmann disease. Clin. Rheumatol., 2007, 26: 1773-1777

[96] Briot K, Roux C. Glucocorticoid-induced osteoporosis. RMD Open, 2015, 1: e000014

[97] Kim YM et al. Clinical characteristics and treatment outcomes in Camurati-Engelmann disease: A case series. Med. (Baltim.), 2018, 97: e0309

[98] Meyers C et al. Heterotopic ossification: A comprehensive review. JBMR, 2019, 3: e10172

[99] Kaplan FS, Al Mukaddam M, Pignolo RJ. Acute unilateral hip pain in fibrodysplasia ossificans progressiva (FOP). Bone, 2018, 109: 115-119

[100] Kitterman JA et al. Neurological symptoms in individuals with fibrodysplasia ossificans progressiva. J. Neurol., 2012, 259: 2636-2643

[101] He JY, Jiang LS, Dai LY. The roles of the sympathetic nervous system in osteoporotic diseases: A review of experimental and clinical studies. Ageing Res. Rev., 2011, 10: 253-263

[102] Schaible HG, Schmidt RF. Activation of groups III and IV sensory units in medial articular nerve by local mechanical stimulation of knee joint. J. Neurophysiol., 1983, 49: 35-44

[103] Coggeshall RE, Hong KA, Langford LA, Schaible HG, Schmidt RF. Discharge characteristics of fine medial articular afferents at rest and during passive movements of inflamed knee joints. Brain Res., 1983, 272: 185-188

[104] Grigg P, Schaible HG, Schmidt RF. Mechanical sensitivity of group III and IV afferents from posterior articular nerve in normal and inflamed cat knee. J. Neurophysiol., 1986, 55: 635-643

[105] Schaible HG, Schmidt RF. Effects of an experimental arthritis on the sensory properties of fine articular afferent units. J. Neurophysiol., 1985, 54: 1109-1122

[106] Kc R et al. PKC delta null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. Ann. Rheum. Dis., 2016, 75: 2133-2141

[107] Ikeuchi M, Wang Q, Izumi M, Tani T. Nociceptive sensory innervation of the posterior cruciate ligament in osteoarthritic knees. Arch. Orthop. Trauma Surg., 2012, 132: 891-895

[108] Suri S et al. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann. Rheum. Dis., 2007, 66: 1423-1428

[109] Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol., 2012, 8: 390-398

[110] Imai S, Tokunaga Y, Maeda T, Kikkawa M, Hukuda S. Calcitonin gene-related peptide, substance P, and tyrosine hydroxylase-immunoreactive innervation of rat bone marrows: An immunohistochemical and ultrastructural investigation on possible efferent and afferent mechanisms. J. Orthop. Res., 1997, 15: 133-140

[111] Malfait AM, Schnitzer TJ. Towards a mechanism-based approach to pain management in osteoarthritis. Nat. Rev. Rheumatol., 2013, 9: 654-664

[112] Zhen GH, Cao X. Targeting TGF beta signaling in subchondral bone and articular cartilage homeostasis. Trends Pharmacol. Sci., 2014, 35: 227-236

[113] Yusuf E, Kortekaas MC, Watt I, Huizinga TWJ, Kloppenburg M. Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review. Ann. Rheum. Dis., 2011, 70: 60-67

[114] Kwoh CK. OSTEOARTHRITIS clinical relevance of bone marrow lesions in OA. Nat. Rev. Rheumatol., 2013, 9: 7-8

[115] Laslett LL et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: A randomised controlled trial. Ann. Rheum. Dis., 2012, 71: 1322-1328

[116] Hamilton JL et al. Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. J. Bone Min. Res., 2016, 31: 911-924

[117] Zheng S, Hunter DJ, Xu J, Ding C. Monoclonal antibodies for the treatment of osteoarthritis. Expert Opin. Biol. Ther., 2016, 16: 1529-1540

[118] Okun A et al. Afferent drive elicits ongoing pain in a model of advanced osteoarthritis. Pain, 2012, 153: 924-933

[119] Okun A et al. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents. Mol. Pain., 2011, 7

[120] Tiwari V et al. Activation of peripheral mu-opioid receptors by Dermorphin [D-Arg2, Lys4] (1-4) amide leads tomodality-preferred inhibition of neuropathic pain. Anesthesiology, 2016, 124: 706-720

[121] Tiwari V et al. Peripherally Acting mu-opioid receptor agonists attenuate ongoing pain-associated behavior and spontaneous neuronal activity after nerve injury in rats. Anesthesiology, 2018, 128: 1220-1236

[122] Frey, E., Karney-Grobe, S., Krolak, T., Milbrandt, J. & DiAntonio, A. TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca²⁺/PKA Signaling. eNeuro 5, ENEURO.0095-18.2018 (2018).

[123] Weng HJ et al. Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron, 2015, 85: 833-846

[124] Shinoda M et al. Involvement of TRPV1 in nociceptive behavior in a rat model of cancer pain. J. Pain., 2008, 9: 687-699

[125] 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

[126] Hu XM et al. Vascular endothelial growth factor a signaling promotes spinal central sensitization and pain-related behaviors in female rats with bone cancer. Anesthesiology, 2019, 131: 1125-1147

[127] Zhang Z et al. Microglial annexin A3 downregulation alleviates bone cancer-induced pain through inhibiting the Hif-1alpha/vascular endothelial growth factor signaling pathway. Pain, 2020, 161: 2750-2762

[128] Nees TA et al. Synovial cytokines significantly correlate with osteoarthritis-related knee pain and disability: Inflammatorymediators of potential clinical relevance. J. Clin. Med., 2019, 8: 1343

[129] Lacout A, Carlier RY, El Hajjam M, Marcy PY. VEGF inhibition as possible therapy in spondyloarthritis patients: Targeting bone remodelling. Med. Hypotheses, 2017, 101: 52-54

[130] Takano S et al. Vascular endothelial growth factor is regulated by the canonical and noncanonical transforming growth factor-beta pathway in synovial fibroblasts derived from osteoarthritis patients. Biomed. Res. Int., 2019, 2019: 6959056

[131] Das V et al. Blockade of Vascular Endothelial Growth Factor Receptor-1 (Flt-1), reveals a novel analgesic for osteoarthritis-induced joint pain. Gene Rep., 2018, 11: 94-100

[132] Esen F, Alhan O, Kuru P, Sahin O. Safety assessment and power analyses in published anti-vascular endothelial growth factor randomized controlled trials. Am. J. Ophthalmol., 2016, 169: 68-72

[133] Castellanos R, Tighe S. Injectable amniotic membrane/umbilical cord particulate for knee osteoarthritis: A prospective, single-center pilot study. Pain. Med., 2019, 20: 2283-2291

[134] Atlas SJ, Deyo RA. Evaluating and managing acute low back pain in the primary care setting. J. Gen. Intern Med., 2001, 16: 120-131

[135] Bogduk N. Evidence-informed management of chronic low back pain with facet injections and radiofrequency neurotomy. Spine J., 2008, 8: 56-64

[136] Kalichman L, Hunter DJ. Lumbar facet joint osteoarthritis: A review. Semin Arthritis Rheum., 2007, 37: 69-80

[137] Park WM, Kim K, Kim YH. Effects of degenerated intervertebral discs on intersegmental rotations, intradiscal pressures, and facet joint forces of the whole lumbar spine. Comput. Biol. Med., 2013, 43: 1234-1240

[138] Kalichman L et al. Facet joint osteoarthritis and low back pain in the community-based population. Spine (Philos. Pa 1976), 2008, 33: 2560-2565

[139] Hicks GE, Morone N, Weiner DK. Degenerative lumbar disc and facet disease in older adults: prevalence and clinical correlates. Spine (Philos. Pa 1976), 2009, 34: 1301-1306

[140] Hu SJ, Xing JL. An experimental model for chronic compression of dorsal root ganglion produced by intervertebral foramen stenosis in the rat. Pain, 1998, 77: 15-23

[141] Pinho-Ribeiro FA, Verri WA Jr., Chiu IM. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol., 2017, 38: 5-19

[142] Kobayashi S, Yoshizawa H, Yamada S. Pathology of lumbar nerve root compression. Part 2: morphological and immunohistochemical changes of dorsal root ganglion. J. Orthop. Res., 2004, 22: 180-188

[143] Zheng L et al. Ciliary parathyroid hormone signaling activates transforming growth factor-beta to maintain intervertebral disc homeostasis during aging. Bone Res., 2018, 6: 21

[144] DiZerega GS, Traylor MM, Alphonso LS, Falcone SJ. Use of temporary implantable biomaterials to reduce leg pain and back pain in patients with sciatica and lumbar disc herniation. Materials, 2010, 3: 3331-3368

[145] Bian Q et al. Excessive activation of TGFbeta by spinal instability causes vertebral endplate sclerosis. Sci. Rep., 2016, 6

[146] Buck D. Amniotic umbilical cord particulate for discogenic pain. J. Am. Osteopath Assoc., 2019, 119: 814-819

[147] Bennett DS. Cryopreserved amniotic membrane and umbilical cord particulate for managing pain caused by facet joint syndrome: A case series. Med. (Baltim.), 2019, 98: e14745

[148] Burckhardt CS. The use of the McGill Pain Questionnaire in assessing arthritis pain. Pain, 1984, 19: 305-314

[149] Shubayev, V. I., Kato, K. & Myers, R. R.. in Translational Pain Research: From Mouse to Man Frontiers in Neuroscience (eds L. Kruger & A. R. Light) (2010).

[150] Toth K et al. Synovial fluid beta-endorphin level in avascular necrosis, rheumatoid arthritis, and osteoarthritis of the femoral head and knee. A controlled pilot study. Clin. Rheumatol., 2011, 30: 537-540

[151] Denko CW, Malemud CJ. Role of the growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseases. Semin. Arthritis Rheum., 2005, 35: 24-34

[152] Wright HL, Bucknall RC, Moots RJ, Edwards SW. Analysis of SF and plasma cytokines provides insights into the mechanisms of inflammatory arthritis and may predict response to therapy. Rheumatol. (Oxf.), 2012, 51: 451-459

[153] Xu ZZ et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nat. Med., 2010, 16: 592-597 591p following 597

[154] Giera M et al. Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. Biochim. Biophys. Acta., 2012, 1821: 1415-1424

[155] Zhen G et al. Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat. Med., 2013, 19: 704-712

[156] Edwards RR et al. Enhanced reactivity to pain in patients with rheumatoid arthritis. Arthritis Res. Ther., 2009, 11: R61

[157] Pollard LC, Ibrahim F, Choy EH, Scott DL. Pain thresholds in rheumatoid arthritis: The effect of tender point counts and disease duration. J. Rheumatol., 2012, 39: 28-31

[158] Hummel T, Schiessl C, Wendler J, Kobal G. Peripheral and central nervous changes in patients with rheumatoid arthritis in response to repetitive painful stimulation. Int. J. Psychophysiol., 2000, 37: 177-183

[159] Hess A et al. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc. Natl. Acad. Sci. USA, 2011, 108: 3731-3736

[160] Wang CR et al. Rare occurrence of inflammatory bowel disease in a cohort of Han Chinese ankylosing spondylitis patients- a single institute study. Sci. Rep., 2017, 7

[161] Yu T et al. Chondrogenesis mediates progression of ankylosing spondylitis through heterotopic ossification. Bone Res., 2021, 9: 19

[162] Langford LA, Schmidt RF. Afferent and efferent axons in the medial and posterior articular nerves of the cat. Anat. Rec., 1983, 206: 71-78

[163] Adams SB et al. Inflammatory cytokines and matrix metalloproteinases in the synovial fluid after intra-articular ankle fracture. Foot Ankle Int., 2015, 36: 1264-1271

[164] Sabsovich I et al. TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I. Pain, 2008, 137: 507-519

[165] Syx D, Tran PB, Miller RE, Malfait AM. Peripheral mechanisms contributing to osteoarthritis pain. Curr. Rheumatol. Rep., 2018, 20: 9

[166] Binshtok AM et al. Nociceptors are interleukin-1beta sensors. J. Neurosci., 2008, 28: 14062-14073

[167] Yeh KT et al. Non-steroid anti-inflammatory drugs are better than acetaminophen on fever control at acute stage of fracture. PLoS One, 2015, 10: e0137225

[168] Sun S et al. No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing. Bone, 2020, 131: 115109

[169] Li Z et al. Fracture repair requires TrkA signaling by skeletal sensory nerves. J. Clin. Invest., 2019, 129: 5137-5150

[170] Zhang R, Liang Y, Wei S. The expressions of NGF and VEGF in the fracture tissues are closely associated with accelerated clavicle fracture healing in patients with traumatic brain injury. Ther. Clin. Risk Manag., 2018, 14: 2315-2322

[171] Davila D, Antoniou A, Chaudhry MA. Evaluation of osseous metastasis in bone scintigraphy. Semin. Nucl. Med., 2015, 45: 3-15

[172] Li BT, Wong MH, Pavlakis N. Treatment and prevention of bone metastases from breast cancer: A comprehensive review of evidence for clinical practice. J. Clin. Med., 2014, 3: 1-24

[173] Aielli F, Ponzetti M, Rucci N. Bone metastasis pain, from the bench to the bedside. Int. J. Mol. Sci., 2019, 20: 280

[174] Majuta LA, Guedon JG, Mitchell SAT, Kuskowski MA, Mantyh PW. Mice with cancer-induced bone pain show a marked decline in day/night activity. Pain. Rep., 2017, 2: e614

[175] Coleman RE et al. Bone metastases. Nat. Rev. Dis. Prim., 2020, 6: 83

[176] Sindhi V, Erdek M. Interventional treatments for metastatic bone cancer pain. Pain. Manag., 2019, 9: 307-315

[177] Falk S, Dickenson AH. Pain and nociception: Mechanisms of cancer-induced bone pain. J. Clin. Oncol., 2014, 32: 1647-1654

[178] Middlemiss T, Laird BJ, Fallon MT. Mechanisms of cancer-induced bone pain. Clin. Oncol. (R. Coll. Radio.), 2011, 23: 387-392

[179] Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin. Cancer Res., 2006, 12: 6243s-6249s

[180] Chiang JS. New developments in cancer pain therapy. Acta. Anaesthesiol. Sin., 2000, 38: 31-36

[181] Edwards KA et al. A kappa opioid receptor agonist blocks bone cancer pain without altering bone loss, tumor size, or cancer cell proliferation in a mouse model of cancer-induced bone pain. J. Pain., 2018, 19: 612-625

[182] Appel CK et al. The Src family kinase inhibitor dasatinib delays pain-related behaviour and conserves bone in a rat model of cancer-induced bone pain. Sci. Rep., 2017, 7

[183] Currie GL et al. Animal models of bone cancer pain: Systematic review and meta-analyses. Pain, 2013, 154: 917-926

[184] Muralidharan A, Smith MT. Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments. Inflammopharmacology, 2013, 21: 339-363

[185] Park SH, Eber MR, Widner DB, Shiozawa Y. Role of the bone microenvironment in the development of painful complications of skeletal metastases. Cancers, 2018, 10: 141

[186] Jimenez-Andrade JM et al. Pathological sprouting of adult nociceptors in chronic prostate cancer-induced bone pain. J. Neurosci., 2010, 30: 14649-14656

[187] Davies MP, Fingas S, Chantry A. Mechanisms and treatment of bone pain in multiple myeloma. Curr. Opin. Support Palliat. Care, 2019, 13: 408-416

[188] Fernandes RS et al. Development of imaging probes for bone cancer in animal models. A systematic review. Biomed. Pharmacother., 2016, 83: 1253-1264

[189] Raja SN, Ringkamp M, Guan Y, Campbell JN, John J. Bonica Award Lecture: Peripheral neuronal hyperexcitability: the “low-hanging” target for safe therapeutic strategies in neuropathic pain. Pain, 2020, 161 Suppl 1 S14-S26

[190] Jeon OH et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med., 2017, 23: 775-781

[191] Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat. Rev. Rheumatol., 2020, 16: 673-688

[192] Chang DS, Hsu E, Hottinger DG, Cohen SP. Anti-nerve growth factor in pain management: current evidence. J. Pain. Res., 2016, 9: 373-383

[193] Hochberg MC. Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies. Osteoarthr. Cartil., 2015, 23 Suppl 1 S18-S21

[194] Ma X, Xu S. TNF inhibitor therapy for rheumatoid arthritis. Biomed. Rep., 2013, 1: 177-184

[195] Kirwan, J. R., Bijlsma, J. W., Boers, M. & Shea, B. J. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst. Rev. 2007, CD006356 (2007).

[196] Lopez-Olivo, M. A. et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst. Rev. 2014, CD000957 (2014).

[197] Vittecoq O et al. Relapse in rheumatoid arthritis patients undergoing dose reduction and withdrawal of biologics: are predictable factors more relevant than predictive parameters? An observational prospective real-life study. BMJ Open, 2019, 9: e031467

[198] Guan Y et al. Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury. Pain, 2008, 138: 318-329

[199] Stein C, Lang LJ. Peripheral mechanisms of opioid analgesia. Curr. Opin. Pharm., 2009, 9: 3-8

[200] Mattia C, Di Bussolo E, Coluzzi F. Non-analgesic effects of opioids: The interaction of opioids with bone and joints. Curr. Pharm. Des., 2012, 18: 6005-6009

[201] Snyder LM et al. Kappa opioid receptor distribution and function in primary afferents. Neuron, 2018, 99: 1274-1288.e6

[202] Woodhams SG, Chapman V, Finn DP, Hohmann AG, Neugebauer V. The cannabinoid system and pain. Neuropharmacology, 2017, 124: 105-120

[203] Agarwal N et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat. Neurosci., 2007, 10: 870-879

[204] Sagar DR et al. Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur. J. Neurosci., 2005, 22: 371-379

[205] Zhang H et al. Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain, 2018, 159: 1814-1823

[206] Starowicz K, Finn DP. Cannabinoids and pain: Sites and mechanisms of action. Adv. Pharm., 2017, 80: 437-475

[207] Yu XH et al. A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain, 2010, 151: 337-344

[208] Kalliomaki J et al. Evaluation of the analgesic efficacy of AZD1940, a novel cannabinoid agonist, on post-operative pain after lower third molar surgical removal. Scand. J. Pain., 2013, 4: 17-22

[209] Hu B et al. A novel rat model of patellofemoral osteoarthritis due to patella baja, or low-lying patella. Nat. Commun., 2019, 25: 2702-2717

[210] Seino D et al. The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint. Pain, 2006, 123: 193-203

[211] Percie du Sert N, Rice AS. Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain. Br. J. Pharm., 2014, 171: 2951-2963

[212] King T, Porreca F. Preclinical assessment of pain: improving models in discovery research. Curr. Top. Behav. Neurosci., 2014, 20: 101-120

[213] Navratilova E, Xie JY, King T, Porreca F. Evaluation of reward from pain relief. Ann. N. Y. Acad. Sci., 2013, 1282: 1-11

[214] King T et al. Unmasking the tonic-aversive state in neuropathic pain. Nat. Neurosci., 2009, 12: 1364-1366

[215] Usoskin D et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat. Neurosci., 2015, 18: 145-153