{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T14:51:33Z","timestamp":1769179893272,"version":"3.49.0"},"reference-count":52,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,12]],"date-time":"2022-08-12T00:00:00Z","timestamp":1660262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoporosis is a disorder, with a largely unknown pathomechanism, that is often marked as a \u201csilent thief\u201d, because it usually only becomes undisguised when fractures occur. This implies that the pathological damage occurs earlier than the sensation of pain. The current authors put forward a non-contact injury model in which the chronic overloading of an earlier autologously microinjured Piezo2 ion channel of the spinal proprioceptor terminals could lead the way to re-injury and earlier aging in a dose-limiting and threshold-driven way. As a result, the aging process could eventually lead the way to the metabolic imbalance of primary osteoporosis in a quad-phasic non-contact injury pathway. Furthermore, it is emphasised that delayed onset muscle soreness, non-contact anterior cruciate injury and osteoporosis could have the same initiating proprioceptive non-contact Piezo2 channelopathy, at different locations, however, with different environmental risk factors and a different genetic predisposition, therefore producing different outcomes longitudinally. The current injury model does not intend to challenge any running pathogenic theories or findings, but rather to highlight a principal injury mechanism.<\/jats:p>","DOI":"10.3390\/ijms23169046","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T01:47:21Z","timestamp":1660528041000},"page":"9046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Osteoporosis in Light of a New Mechanism Theory of Delayed Onset Muscle Soreness and Non-Contact Anterior Cruciate Ligament Injury"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-1306","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Sonkodi","sequence":"first","affiliation":[{"name":"Department of Health Sciences and Sport Medicine, Hungarian University of Sports Science, 1123 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Bardoni","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyula","family":"Po\u00f3r","sequence":"additional","affiliation":[{"name":"National Institute of Locomotor Diseases and Disabilities, 1023 Budapest, Hungary"},{"name":"Section of Rheumatology and Physiotherapy, Department of Internal Medicine and Haematology, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,12]]},"reference":[{"key":"ref_1","first-page":"97","article-title":"Bone pain mechanism in osteoporosis: A narrative review","volume":"13","author":"Mattia","year":"2016","journal-title":"Clin. Cases Miner. Bone Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/ejn.12462","article-title":"The neurobiology of skeletal pain","volume":"39","author":"Mantyh","year":"2014","journal-title":"Eur. J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1249\/00005768-199205000-00004","article-title":"Muscle function after exercise-induced muscle damage and rapid adaptation","volume":"24","author":"Clarkson","year":"1992","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_4","first-page":"311","article-title":"Epidemiology of Collegiate Injuries for 15 Sports: Summary and Recommendations for Injury Prevention Initiatives","volume":"42","author":"Hootman","year":"2007","journal-title":"J. Athl. Train."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Resch, M.D., and Hortob\u00e1gyi, T. (2022). Is the Sex Difference a Clue to the Pathomechanism of Dry Eye Disease? Watch out for the NGF-TrkA-Piezo2 Signaling Axis and the Piezo2 Channelopathy. J. Mol. Neurosci.","DOI":"10.1007\/s12031-022-02015-9"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Berkes, I., and Koltai, E. (2020). Have We Looked in the Wrong Direction for More Than 100 Years? Delayed Onset Muscle Soreness Is, in Fact, Neural Microdamage Rather Than Muscle Damage. Antioxidants, 9.","DOI":"10.3390\/antiox9030212"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sonkodi, B. (2021). Delayed Onset Muscle Soreness (DOMS): The Repeated Bout Effect and Chemotherapy-Induced Axonopathy May Help Explain the Dying-Back Mechanism in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases. Brain Sci., 11.","DOI":"10.3390\/brainsci11010108"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1111\/j.1460-9568.2011.07652.x","article-title":"Terminal arbor degeneration\u2014A novel lesion produced by the antineoplastic agent paclitaxel","volume":"33","author":"Bennett","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Kopa, Z., and Nyir\u00e1dy, P. (2021). Post Orgasmic Illness Syndrome (POIS) and Delayed Onset Muscle Soreness (DOMS): Do They Have Anything in Common?. Cells, 10.","DOI":"10.3390\/cells10081867"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Bardoni, R., Hangody, L., Rad\u00e1k, Z., and Berkes, I. (2021). Does Compression Sensory Axonopathy in the Proximal Tibia Contribute to Noncontact Anterior Cruciate Ligament Injury in a Causative Way?\u2014A New Theory for the Injury Mechanism. Life, 11.","DOI":"10.3390\/life11050443"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.cmet.2019.08.012","article-title":"Mediation of the Acute Stress Response by the Skeleton","volume":"30","author":"Berger","year":"2019","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1097\/00007632-199801150-00004","article-title":"Mechanoreceptor Endings in Human Thoracic and Lumbar Facet Joints","volume":"23","author":"McLain","year":"1998","journal-title":"Spine"},{"key":"ref_13","first-page":"147","article-title":"Mechanoreceptor endings of the cervical, thoracic, and lumbar spine","volume":"15","author":"McLain","year":"1995","journal-title":"Iowa Orthop. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"644929","DOI":"10.3389\/fphys.2021.644929","article-title":"Piezo2 Knockdown Inhibits Noxious Mechanical Stimulation and NGF-Induced Sensitization in A-Delta Bone Afferent Neurons","volume":"12","author":"Nencini","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1016\/j.celrep.2017.07.073","article-title":"The Proprioceptive System Regulates Morphologic Restoration of Fractured Bones","volume":"20","author":"Blecher","year":"2017","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20170327","DOI":"10.1098\/rstb.2017.0327","article-title":"New functions for the proprioceptive system in skeletal biology","volume":"373","author":"Blecher","year":"2018","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Heged\u0171s, \u00c1., Kopper, B., and Berkes, I. (2022). Significantly Delayed Medium-Latency Response of the Stretch Reflex in Delayed-Onset Muscle Soreness of the Quadriceps Femoris Muscles Is Indicative of Sensory Neuronal Microdamage. J. Funct. Morphol. Kinesiol., 7.","DOI":"10.3390\/jfmk7020043"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1515\/med-2022-0444","article-title":"Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes\u2014Watch out for Piezo2","volume":"17","author":"Sonkodi","year":"2022","journal-title":"Open Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1038\/s41467-020-16971-6","article-title":"Piezo2 expressed in proprioceptive neurons is essential for skeletal integrity","volume":"11","author":"Assaraf","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cophys.2021.01.004","article-title":"More than movement: The proprioceptive system as a new regulator of musculoskeletal biology","volume":"20","author":"Bornstein","year":"2021","journal-title":"Curr. Opin. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4138","DOI":"10.1007\/s00167-021-06470-6","article-title":"Knee position at the moment of bone bruise could reflect the late phase of non-contact anterior cruciate ligament injury rather than the mechanisms leading to ligament failure","volume":"29","author":"Grassi","year":"2021","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1023\/A:1019996809849","article-title":"Gate Control Theory Reconsidered","volume":"3","author":"Sufka","year":"2002","journal-title":"Brain Mind"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sonkodi, B., Varga, E., Hangody, L., Po\u00f3r, G., and Berkes, I. (2021). Finishing stationary cycling too early after anterior cruciate ligament reconstruction is likely to lead to higher failure. BMC Sports Sci. Med. Rehabil., 13.","DOI":"10.1186\/s13102-021-00377-y"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.csm.2012.08.017","article-title":"The Role of ACL Injury in the Development of Posttraumatic Knee Osteoarthritis","volume":"32","author":"Friel","year":"2013","journal-title":"Clin. Sports Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e03963","DOI":"10.1016\/j.heliyon.2020.e03963","article-title":"Mechanism of aspirin-induced inhibition on the secondary hyperalgesia in osteoarthritis model rats","volume":"6","author":"Niibori","year":"2020","journal-title":"Heliyon"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1744806920975950","DOI":"10.1177\/1744806920975950","article-title":"ASIC3 inhibition modulates inflammation-induced changes in the activity and sensitivity of A\u03b4 and C fiber sensory neurons that innervate bone","volume":"16","author":"Morgan","year":"2020","journal-title":"Mol. Pain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.pain.2008.01.020","article-title":"Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice","volume":"137","author":"Ikeuchi","year":"2008","journal-title":"Pain"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115272","DOI":"10.1016\/j.bone.2020.115272","article-title":"An understanding of bone pain: A narrative review","volume":"134","author":"Oostinga","year":"2020","journal-title":"Bone"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11460","DOI":"10.1038\/ncomms11460","article-title":"Evidence for the involvement of ASIC3 in sensory mechanotransduction in proprioceptors","volume":"7","author":"Lin","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1038\/nn.4162","article-title":"Piezo2 is the principal mechanotransduction channel for proprioception","volume":"18","author":"Woo","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1111\/j.1601-183X.2011.00683.x","article-title":"Expressing acid-sensing ion channel 3 in the brain alters acid-evoked currents and impairs fear conditioning","volume":"10","author":"Vralsted","year":"2011","journal-title":"Genes Brain Behav."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2001611118","DOI":"10.1073\/pnas.2001611118","article-title":"Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis","volume":"118","author":"Lee","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Xu, X., Liu, S., Liu, H., Ru, K., Jia, Y., Wu, Z., Liang, S., Khan, Z., Chen, Z., and Qian, A. (2021). Piezo Channels: Awesome Mechanosensitive Structures in Cellular Mechanotransduction and Their Role in Bone. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126429"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nature13701","article-title":"Piezo1 integration of vascular architecture with physiological force","volume":"515","author":"Li","year":"2014","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.neurobiolaging.2010.08.008","article-title":"The effect of aging on the density of the sensory nerve fiber innervation of bone and acute skeletal pain","volume":"33","author":"Mantyh","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12990-015-0067-5","article-title":"Transient, Activity Dependent Inhibition of Transmitter Release from Low Threshold Afferents Mediated by GABAA Receptors in Spinal Cord Lamina III\/IV","volume":"11","author":"Betelli","year":"2015","journal-title":"Mol. Pain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"172475","DOI":"10.1016\/j.ejphar.2019.172475","article-title":"The therapeutic potential of GABA in neuron-glia interactions of cancer-induced bone pain","volume":"858","author":"Ge","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6208","DOI":"10.1038\/s41467-021-26270-3","article-title":"Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission","volume":"12","author":"Yeo","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"73462","DOI":"10.18632\/oncotarget.11867","article-title":"GPR30 disrupts the balance of GABAergic and glutamatergic transmission in the spinal cord driving to the development of bone cancer pain","volume":"7","author":"Luo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s42003-020-0766-y","article-title":"Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis","volume":"3","author":"Wang","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1744806917745465","DOI":"10.1177\/1744806917745465","article-title":"Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur","volume":"13","author":"Chartier","year":"2017","journal-title":"Mol. Pain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/BF02555041","article-title":"Sex-and age-related changes in bone and serum osteocalcin","volume":"46","author":"Vanderschueren","year":"1990","journal-title":"Calcif. Tissue Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.bone.2006.04.033","article-title":"Osteoclasts play a part in pain due to the inflammation adjacent to bone","volume":"39","author":"Nagae","year":"2006","journal-title":"Bone"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5231","DOI":"10.1113\/JP280324","article-title":"Influence of age on the frequency characteristics of the soleus muscle response to Achilles tendon vibration during standing","volume":"598","author":"Mildren","year":"2020","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/jnc.15006","article-title":"Involvement of the Hsp70\/TLR4\/IL-6 and TNF-\u03b1 pathways in delayed-onset muscle soreness","volume":"155","author":"Veras","year":"2020","journal-title":"J. Neurochem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"de Sire, A., Marotta, N., Ferrillo, M., Agostini, F., Sconza, C., Lippi, L., Respizzi, S., Giudice, A., Invernizzi, M., and Ammendolia, A. (2022). Oxygen-Ozone Therapy for Reducing Pro-Inflammatory Cytokines Serum Levels in Musculoskeletal and Temporomandibular Disorders: A Comprehensive Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052528"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, X., Zhou, Z.Y., Zhang, Y.Y., and Yang, H.L. (2016). IL-6 Contributes to the Defective Osteogenesis of Bone Marrow Stromal Cells from the Vertebral Body of the Glucocorticoid-Induced Osteoporotic Mouse. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154677"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Papathanasiou, I., Michalitsis, S., Hantes, M.E., Vlychou, M., Anastasopoulou, L., Malizos, K.N., and Tsezou, A. (2016). Molecular changes indicative of cartilage degeneration and osteoarthritis development in patients with anterior cruciate ligament injury. BMC Musculoskelet. Disord., 17.","DOI":"10.1186\/s12891-016-0871-8"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Juskovic, A., Nikolic, M., Ljujic, B., Matic, A., Zivkovic, V., Vucicevic, K., Milosavljevic, Z., Vojinovic, R., Jovicic, N., and Zivanovic, S. (2022). Effects of Combined Allogenic Adipose Stem Cells and Hyperbaric Oxygenation Treatment on Pathogenesis of Osteoarthritis in Knee Joint Induced by Monoiodoacetate. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147695"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eaat9892","DOI":"10.1126\/scitranslmed.aat9892","article-title":"PIEZO2 mediates injury-induced tactile pain in mice and humans","volume":"10","author":"Szczot","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1007\/s00198-018-4536-3","article-title":"Understanding osteoporotic pain and its pharmacological treatment: Supplementary presentation","volume":"29","author":"Vellucci","year":"2018","journal-title":"Osteoporos. Int."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"De Sire, A., Marotta, N., Lippi, L., Scaturro, D., Far\u00ec, G., Liccardi, A., Moggio, L., Letizia Mauro, G., Ammendolia, A., and Invernizzi, M. (2021). Pharmacological Treatment for Acute Traumatic Musculoskeletal Pain in Athletes. Medicina, 57.","DOI":"10.3390\/medicina57111208"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9046\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:08:03Z","timestamp":1760141283000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,12]]},"references-count":52,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23169046"],"URL":"https:\/\/doi.org\/10.3390\/ijms23169046","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,12]]}}}