Coronavirus disease 2019 (COVID-19) is an emerging, worldwide infectious disease pandemic that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By April 27, 2020, the virus had spread to at least 185 countries or regions and infected >3 million people, causing at least 210,000 deaths1. The severity of COVID-19 can be roughly categorized into 3 groups based on the severity of the initial infection2,3. Mild COVID-19, which, along with asymptomatic COVID-19, comprises the majority of cases, is characterized by symptoms such as fever, shortness of breath, gastrointestinal distress, malaise, headaches, and a loss of taste and smell. Patients with mild COVID-19 may or may not seek medical treatment and can sometimes present with mild pneumonia. Severely ill patients require hospitalization for treatment of the infection because of respiratory issues, and critical patients are a subset of the severely ill patients who experience respiratory failure that requires mechanical ventilation support. The percentages of patients vary, but mild cases are reported to be approximately 80%, severe cases are 14%, and critical cases are 6%2,3. However, as many countries prioritize testing only for hospitalized patients, determining the exact percentages of patients in the general population is challenging4,5.
SARS-CoV-2 belongs to the coronavirus family of positive-sense, single-stranded RNA viruses6. In addition to SARS-CoV-2, there are 6 other strains of coronavirus that are known to infect humans, including 4 less severe strains that cause mild symptoms, as well as the more pathogenic viruses SARS-CoV-1, which causes severe acute respiratory syndrome (SARS), and MERS-CoV, which is responsible for Middle East respiratory syndrome (MERS)6. There is a high degree of homology between the genetic sequences of SARS-CoV-1 and SARS-CoV-2 and extensive similarity in the predicted viral:human interactome between the 2 strains7,8. Both SARS-CoV-1 and SARS-CoV-2 enter cells via the angiotensin-converting enzyme 2 (ACE2) receptor using the serine protease TMPRSS2 (transmembrane protease, serine 2)9. Following receptor binding, proteolytic cleavage of the viral S protein by TMPRRS2 exposes a fusion peptide signal that permits mixing of viral and human membranes and release of viral RNA into the cytoplasm10. Once the viral RNA has access to the cytoplasm, translation of viral proteins and replication of viral RNA can occur, ultimately leading to the assembly of virions that are released from infected cells by exocytosis10. Several proteins encoded by viral RNA can also interact with various human cellular proteins to disrupt their function. Among the human proteins and pathways predicted to be targeted by SARS-CoV-2 proteins are those involved with intracellular vesicle trafficking, ubiquitin ligases, inflammatory signaling, nuclear transport, cytoskeletal stability, and mitochondrial respiration7,8,11. Therefore, the viral infection of cells can lead to the production of more virus and can severely disrupt fundamental cellular functions and lead to eventual apoptosis7,8,11. These apoptotic cells then contribute to tissue-level dysfunction and can also amplify local inflammation.
Studies from patients who contracted moderate and severe SARS infections have indicated a substantial musculoskeletal burden of this disease, including skeletal muscle, neurological, bone, and joint disorders12-14. Extended ventilator times are also known to induce proinflammatory conditions that lead to muscle and bone frailty, which can reduce overall quality of life15,16. In addition to directly infecting cells outside of the respiratory tract, the inflammatory response in the airway can also lead to systemic inflammation that can impact nearly every organ system, including the musculoskeletal system17,18. The cytokines and signaling molecules induced by the infection include C-X-C motif chemokine 10 (CXCL10), interferon gamma (IFN-γ), interleukin 1 beta (IL-1β), IL-6, IL-8, IL-17, and tumor necrosis factor alpha (TNF-α)18,19. Although clinical data on patients with COVID-19 following the acute care episode have been limited, there are compelling early signs of musculoskeletal dysfunction in patients recovering from COVID-19 and known musculoskeletal pathologies in patients who had SARS. Although not identical, computational biology and in vitro experimental studies have shown a high degree of similarity between the pathological response to SARS-CoV-1 and SARS-CoV-2 infection. Therefore, the purpose of this article was to summarize the known musculoskeletal sequelae of SARS and early reports for COVID-19 and analyze the epidemiological data along with molecular modeling and biochemical signaling studies to aid in the prediction of musculoskeletal targets and long-term musculoskeletal consequences of COVID-19 infection.
Identifying Potential Musculoskeletal Cellular Targets for Direct SARS-CoV-2 Infection
During the initial respiratory infection, SARS-CoV-2 is thought to predominantly infect type-II pneumocytes that line the respiratory epithelium, which express ACE2 and TMPRSS217. Although the respiratory tract appears to be the primary site of infection, the compromised alveolar epithelium in some patients with COVID-19 can lead to the development of viremias20. Therefore, cells in other tissues may be susceptible to direct viral infection. To identify if musculoskeletal tissues express ACE2 and TMPRSS2, we performed a secondary analysis of previously published human genetic sequencing data. For skeletal muscle, cartilage, meniscus, and synovium, we used single-cell RNA sequencing (scRNAseq) data sets21-24, which allow for the determination of gene expression in specific cell types that constitute the tissue. We could not identify scRNAseq data for human bone and instead used bulk RNA sequencing (RNAseq) libraries of homogenized composite cortical and trabecular bone tissue and osteoblast-enriched cortical bone fractions25. Data from human airway epithelium26 are shown as a control. Methods related to ACE2 and TMPRSS2 gene expression analysis can be found in the Appendix.
Within the respiratory airway epithelium, a small portion of B cells, mast cells, macrophages, type-1 and type-2 alveolar cells, and T cells express ACE2 and TMPRSS2 (Fig. 1-A). For human skeletal muscle tissue, numerous cell types express TMPRSS2, including vascular cells such as endothelial cells, smooth muscle cells, pericytes, muscle stem cells (satellite cells), macrophages, adaptive immune cells (B, T, or natural killer cells), and myonuclei (muscle fibers) (Fig. 1-A). However, only smooth muscle cells and pericytes express ACE2. Several cells in the synovium express ACE2 and TMPRSS2, including fibroblasts, monocytes, B cells, and T cells (Fig. 1-A). For articular cartilage, proliferative, hypertrophic, and effector chondrocytes (which are a subset of chondrocytes that appear to have a high level of metabolic activity) express ACE2, and only homeostatic chondrocytes (which appear to control circadian clock rhythm in cartilage) express TMPRSS2 (Fig. 1-A). In the meniscus, a small fraction of cartilage progenitors and regulatory fibrochondrocytes express ACE2, with no TMPRSS2 detected (Fig. 1-A). Whole-tissue RNAseq identified that ACE2 was expressed in nearly every sample of composite unenriched cortical and trabecular bone and in osteoblast-enriched samples (Fig. 1-B). TMPRSS2 was nearly undetectable in composite bone tissue, and TMPRSS2 was expressed in all osteoblast-enriched samples (Fig. 1-B). The bone cell marker osterix (Sp7) is shown as a control (Fig. 1-B). Human tendon and ligament transcriptional data sets were not available, but we noted an absence of ACE2 and TMPRSS2 transcript production in mouse and rat limb tendon scRNAseq and bulk RNAseq gene atlases27,28. Although SARS-CoV-2 has not been specifically detected in these tissues, these findings indicate skeletal muscle, synovium, and cortical bone as potential sites of direct SARS-CoV-2 infection. Cartilage could potentially be a target, but this would involve viral priming and entry in a non-cell autonomous paracrine manner. Further studies that use RNA in situ hybridization or immunohistochemistry using antibodies against viral proteins would clarify the presence or absence of virus in these tissues.
Clinical Presentation and Symptoms
Myalgias and generalized weakness have been reported to occur in one-quarter to one-half of symptomatic patients with COVID-1929-31. Although some data have suggested that the occurrence of muscle pain does not increase with COVID-19 severity32, in patients with abnormal computed tomographic (CT) or radiographic imaging of the lungs, myalgias were an important predictive factor for the severity of the overall disease33. In a study of 214 hospitalized patients with COVID-19 in Wuhan, People’s Republic of China, 19% of patients had creatine kinase (CK) levels of >200 U/L (a commonly used cutoff for clinically elevated CK), with an upper range of 12,216 U/L34. Loosely defined neurological symptoms that impact motor control and muscle function were reported in up to 36% of patients34. Extensive myalgias and muscle dysfunction have also been reported in patients with SARS30,35-37. The mean CK level of patients with mild and moderate SARS was 269 U/L, and it reached a mean of 609 U/L in those with a severe course of the disease38. Compared with age-matched healthy controls, approximately 2 to 3 months after discharge from the hospital, patients with moderate and severe SARS had a 32% reduction in grip strength and a 13% reduction in the distance walked over a 6-minute period of time39. This suggests that the SARS infection leads to deficits in both muscle strength and endurance, likely due to the proinflammatory effects of the viral infection and the deconditioning that occurs during the convalescent period. The reduced functional capacity of these patients corresponded with decreases in several indices of health-related quality of life. There were occupational impacts as well, with only 40% of patients returning to work by 2 to 3 months after the acute episode of care39,40.
Because of the emerging nature of COVID-19, the mechanistic effects of the infection on skeletal muscle are not fully understood. In a mouse model of SARS, within 4 days of infection, there was a rapid 20% decrease in body mass41. Using muscle tissue collected postmortem from patients with SARS who had died, several small studies have provided insight into the nature of muscle dysfunction as a result of SARS-CoV-1 infection12,42,43. Widespread muscle fiber atrophy was noted, with sporadic and focal muscle fiber necrosis and immune cell infiltration12,42. Electron micrographs revealed myofibril disarray and Z disc streaming12, which would disrupt force transmission as noted in other muscle diseases44,45. Neuronal demyelination has also been reported in patients with SARS42, which may also contribute to muscle weakness and fatigue.
In addition to potential direct viral infection, the cytokines and proinflammatory signaling molecules induced by the infection could lead to pathological changes in skeletal muscle tissue. C-reactive protein (CRP) is a commonly used biomarker for general inflammation, and numerous studies have demonstrated that severely ill patients with COVID-19 have CRP levels severalfold higher than healthy controls4,46-48. Several of the proinflammatory signaling molecules known to be elevated in patients with COVID-1918 can also impact skeletal muscle. IFN-γ, IL-1β, IL-6, IL-17, and TNF-α can directly induce muscle fiber proteolysis and decrease protein synthesis49-53. Satellite cells are progenitor cells that directly contribute to muscle fiber growth, a process that is important as patients recover from COVID-19, and IL-1β and TNF-α can block the proliferation and differentiation of these cells50,54,55. IL-1β and IL-6 can induce muscle fibroblast activity and lead to fibrosis, which could impair muscle force production and increase injury susceptibility56,57. Additionally, corticosteroids were extensively used to limit acute inflammation in patients with SARS14,58,59, and these drugs can directly induce muscle atrophy and weakness60. However, the U.S. Centers for Disease Control and Prevention (CDC) advises against the routine use of corticosteroids for COVID-1961, and corticosteroid-induced muscle impairment may therefore be less of a factor in the recovery of patients with COVID-19.
Bone and Joint
Clinical Presentation and Symptoms
Less is known about bone and joint than skeletal muscle disorders in patients with COVID-19. Arthralgias are commonly reported in patients with COVID-19, but are often combined with myalgias62-64, making it challenging to specifically identify arthralgia prevalence. Arthralgias have also been reported in patients with SARS, as well as reduced bone mineral density (BMD)14,65. The reduced BMD observed in patients with SARS was largely thought to be dependent on the extent and duration of treatment with corticosteroids, which were a mainstay therapy that attempted to reduce inflammation during the initial infection and subsequent early rehabilitation and recovery period14,65. However, decreased BMD has also been reported in other acute critical illnesses and may occur independently of treatment with corticosteroids15,66. Osteonecrosis has been frequently reported in patients with severe SARS, with rates from 5% to 58%14,67. The majority of these cases involve the femoral head, although the knee, humeral head, talus, calcaneus, and other anatomical sites were affected in lower frequencies14. Similar to osteoporosis, patients who had higher or longer doses of corticosteroids had an elevated risk of developing osteonecrosis14,58,68. Hypercoagulability has also been noted in both patients with COVID-19 and those with SARS69-71, leading to large-vessel stroke in some patients72. The SARS-CoV-1 infection can also induce the expression of the E3 ubiquitin ligase gene TRIM55 in vascular smooth muscle cells, which is associated with leukocyte aggregation and blood vessel inflammation73. The combination of hypercoagulability, leukocyte aggregation, and vessel inflammation may impair bone microvascular blood flow and contribute to the development of osteonecrosis.
Systemic inflammation may also play a role in bone and joint tissue physiology in patients with COVID-19. Of the cytokines known to be induced as a result of COVID-19, CXCL10, IL-17, and TNF-α have established roles in inducing osteoclastogenesis and decreasing osteoblast proliferation and differentiation, leading to a net reduction in BMD74-76. IL-1β, IL-6, and TNF-α can lead to chondrolysis, which could result in arthralgias or progression of osteoarthritis in some patients77-79. Similarly, IL-1β, IL-17, and TNF-α are thought to promote inflammation in tendinopathy and can impair the normal biological activity of tenocytes80-82, resulting in impaired matrix remodeling and potential exacerbation of degenerative tendon disorders.
Early findings in patients with COVID-19 have identified musculoskeletal sequelae associated with this disease. Based on these reports, the epidemiological data from patients with SARS during the pandemic of 2002 to 2004, the genetic and pathological similarities between SARS-CoV-1 and SARS-CoV-2, and the frequent reporting of sarcopenia and osteoporosis in other critical illnesses15,16,66,83, we think that it is appropriate to anticipate short-term and long-term musculoskeletal complications in patients with moderate and severe COVID-19 (Fig. 2). Conservative rehabilitation programs have been shown to improve functional recovery in patients with SARS and are effective in other critical illnesses as well40,84. A randomized controlled trial of 133 patients with SARS demonstrated that a 6-week progressive aerobic and resistance exercise program, consisting of 60 to 90-minute sessions that occurred 4 to 5 times per week, could be effective in improving strength and function40. Compared with baseline, patients who completed the program demonstrated a 10% increase in predicted VO2max, a 17% improvement in grip strength, a 38% increase in shoulder flexion strength, and a 250% increase in hip extension strength40. The program also led to a 53% increase in curl-up repetitions per minute and a 91% increase in push-up repetitions per minute40. Similar rehabilitation programs, using both aerobic and resistance training to decrease fatigue and increase strength, would likely be beneficial for skeletal muscle, bone, joint, connective tissue, and cardiopulmonary health in patients with COVID-19. Because of the adverse effects of corticosteroids on skeletal muscle and bone, patients who do undergo corticosteroid treatment should be monitored for exacerbated musculoskeletal symptoms. A greater number of immunotherapies, such as IL-1 and IL-6 inhibitors, are being used off-label and in clinical trials to treat acute inflammation in patients with COVID-1985,86, and these agents may also impact recovery of musculoskeletal function. Additionally, there are single nucleotide polymorphisms in various proinflammatory genes, such as IL-1β, IL-6, and IL-8, that can impact their biological activity and could contribute to the variation in outcomes to respiratory diseases87. Cohort studies focused on the musculoskeletal health of patients recovering from COVID-19 would provide important insight in identifying long-term outcomes of this devastating disease. Furthermore, outcome studies in patients with preexisting musculoskeletal diseases and those undergoing an orthopaedic surgical procedure during their illness will provide critical knowledge about mitigating the musculoskeletal consequences of COVID-19.
Supporting material provided by the authors is posted with the online version of this article as a data supplement at jbjs.org (https://links.lww.com/JBJS/F928).
1. Johns Hopkins University. Coronavirus resource center. Accessed 2020 Apr 27. https://coronavirus.jhu.edu
2. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. [Epub ahead of print].
3. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-20. Epub 2020 Feb 28.
4. Zhao X, Zhang B, Li P, Ma C, Gu J, Hou P, Guo Z, Wu H, Bai Y. Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis. 2020 Mar 20. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.03.17.20037572v1
5. Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, Satlin MJ, Campion TR Jr, Nahid M, Ringel JB, Hoffman KL, Alshak MN, Li HA, Wehmeyer GT, Rajan M, Reshetnyak E, Hupert N, Horn EM, Martinez FJ, Gulick RM, Safford MM. Clinical characteristics of COVID-19 in New York City. N Engl J Med. 2020 Apr 17. [Epub ahead of print].
6. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019 Mar;17(3):181-92.
7. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O’Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Huettenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O’Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d’Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 Apr 30. [Epub ahead of print].
8. Guzzi PH, Mercatelli D, Ceraolo C, Giorgi FM. Master regulator analysis of the SARS-CoV-2/human interactome. J Clin Med. 2020 Apr 1;9(4):E982.
9. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. Epub 2020 Mar 5.
10. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1-23.
11. Srinivasan S, Cui H, Gao Z, Liu M, Lu S, Mkandawire W, Narykov O, Sun M, Korkin D. Structural genomics of SARS-CoV-2 indicates evolutionary conserved functional regions of viral proteins. Viruses. 2020 Mar 25;12(4):E360.
12. Leung TW, Wong KS, Hui AC, To KF, Lai ST, Ng WF, Ng HK. Myopathic changes associated with severe acute respiratory syndrome: a postmortem case series. Arch Neurol. 2005 Jul;62(7):1113-7.
13. Tsai LK, Hsieh ST, Chang YC. Neurological manifestations in severe acute respiratory syndrome. Acta Neurol Taiwan. 2005 Sep;14(3):113-9.
14. Griffith JF. Musculoskeletal complications of severe acute respiratory syndrome. Semin Musculoskelet Radiol. 2011 Nov;15(5):554-60. Epub 2011 Nov 11.
15. Orford NR, Pasco JA, Kotowicz MA. Osteoporosis and the critically ill patient. Crit Care Clin. 2019 Apr;35(2):301-13. Epub 2019 Jan 28.
16. Kizilarslanoglu MC, Kuyumcu ME, Yesil Y, Halil M. Sarcopenia in critically ill patients. J Anesth. 2016 Oct;30(5):884-90. Epub 2016 Jul 4.
17. Cheng H, Wang Y, Wang GQ. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. J Med Virol. 2020 Mar 27. [Epub ahead of print].
18. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. Epub 2020 Jan 24.
19. Liu J, Li S, Liu J, Liang B, Wang X, Wang H, Li W, Tong Q, Yi J, Zhao L, Xiong L, Guo C, Tian J, Luo J, Yao J, Pang R, Shen H, Peng C, Liu T, Zhang Q, Wu J, Xu L, Lu S, Wang B, Weng Z, Han C, Zhu H, Zhou R, Zhou H, Chen X, Ye P, Zhu B, Wang L, Zhou W, He S, He Y, Jie S, Wei P, Zhang J, Lu Y, Wang W, Zhang L, Li L, Zhou F, Wang J, Dittmer U, Lu M, Hu Y, Yang D, Zheng X. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020 Apr 18;55:102763. [Epub ahead of print].
20. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9490-6. Epub 2020 Apr 6.
21. De Micheli AJ, Spector JA, Elemento O, Cosgrove BD. A reference single-cell transcriptomic atlas of human skeletal muscle tissue reveals bifurcated muscle stem cell populations. Accessed 2020 Apr 27. https://www.biorxiv.org/content/10.1101/2020.01.21.914713v1
22. Ji Q, Zheng Y, Zhang G, Hu Y, Fan X, Hou Y, Wen L, Li L, Xu Y, Wang Y, Tang F. Single-cell RNA-seq analysis reveals the progression of human osteoarthritis. Ann Rheum Dis. 2019 Jan;78(1):100-10. Epub 2018 Jul 19.
23. Sun H, Wen X, Li H, Wu P, Gu M, Zhao X, Zhang Z, Hu S, Mao G, Ma R, Liao W, Zhang Z. Single-cell RNA-seq analysis identifies meniscus progenitors and reveals the progression of meniscus degeneration. Ann Rheum Dis. 2020 Mar;79(3):408-17. Epub 2019 Dec 23.
24. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, Goodman SM, Tabechian D, Hughes LB, Salomon-Escoto K, Watts GFM, Jonsson AH, Rangel-Moreno J, Meednu N, Rozo C, Apruzzese W, Eisenhaure TM, Lieb DJ, Boyle DL, Mandelin AM 2nd, Boyce BF, DiCarlo E, Gravallese EM, Gregersen PK, Moreland L, Firestein GS, Hacohen N, Nusbaum C, Lederer JA, Perlman H, Pitzalis C, Filer A, Holers VM, Bykerk VP, Donlin LT, Anolik JH, Brenner MB, Raychaudhuri S; Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019 Jul;20(7):928-42. Epub 2019 May 6.
25. Weivoda MM, Chew CK, Monroe DG, Farr JN, Atkinson EJ, Geske JR, Eckhardt B, Thicke B, Ruan M, Tweed AJ, McCready LK, Rizza RA, Matveyenko A, Kassem M, Andersen TL, Vella A, Drake MT, Clarke BL, Oursler MJ, Khosla S. Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism. Nat Commun. 2020 Jan 7;11(1):87.
26. Vieira Braga FA, Kar G, Berg M, Carpaij OA, Polanski K, Simon LM, Brouwer S, Gomes T, Hesse L, Jiang J, Fasouli ES, Efremova M, Vento-Tormo R, Talavera-López C, Jonker MR, Affleck K, Palit S, Strzelecka PM, Firth HV, Mahbubani KT, Cvejic A, Meyer KB, Saeb-Parsy K, Luinge M, Brandsma CA, Timens W, Angelidis I, Strunz M, Koppelman GH, van Oosterhout AJ, Schiller HB, Theis FJ, van den Berge M, Nawijn MC, Teichmann SA. A cellular census of human lungs identifies novel cell states in health and in asthma. Nat Med. 2019 Jul;25(7):1153-63. Epub 2019 Jun 17.
27. Disser NP, Ghahramani GC, Swanson JB, Wada S, Chao ML, Rodeo SA, Oliver DJ, Mendias CL. Widespread diversity in the transcriptomes of functionally divergent limb tendons. J Physiol. 2020 Apr;598(8):1537-50. Epub 2020 Mar 30.
28. De Micheli AJ, Swanson JB, Disser NP, Martinez LM, Walker NR, Oliver DJ, Cosgrove BD, Mendias CL. Single-cell transcriptomics identify extensive heterogeneity in the cellular composition of mouse Achilles tendons. 2020 Apr 2. Accessed 2020 Apr 27. https://www.biorxiv.org/content/10.1101/801266v3
29. Nasiri MJ, Haddadi S, Tahvildari A, Farsi Y, Arbabi M, Hasanzadeh S, Jamshidi P, Murthi M, Mirsaeidi M. COVID-19 clinical characteristics, and sex-specific risk of mortality: systematic review and meta-analysis. 2020 Mar 26. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.03.24.20042903v1
30. Xu P, Sun G-D, Li Z-Z. Clinical characteristics of two human to human transmitted coronaviruses: corona virus disease 2019 versus Middle East respiratory syndrome coronavirus. 2020 Mar 10. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.03.08.20032821v1
31. Heydari K, Rismantab S, Shamshirian A, Lotfi P, Shadmehri N, Houshmand P, Zahedi M, Shamshirian D, Bathaeian S, Alizadeh-Navaei R. Clinical and paraclinical characteristics of COVID-19 patients: a systematic review and meta-analysis. 2020 Mar 30. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.03.26.20044057v1
32. Chen X, Zheng F, Qing Y, Ding S, Yang D, Lei C, Yin Z, Zhou X, Jiang D, Zuo Q, He J, Lv J, Chen P, Chen Y, Peng H, Li H, Xie Y, Liu J, Zhou Z, Luo H. Epidemiological and clinical features of 291 cases with coronavirus disease 2019 in areas adjacent to Hubei, China: a double-center observational study. 2020 Mar 6. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.03.03.20030353v1
33. Zhang X, Cai H, Hu J, Lian J, Gu J, Zhang S, Ye C, Lu Y, Jin C, Yu G, Jia H, Zhang Y, Sheng J, Li L, Yang Y. Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings. Int J Infect Dis. 2020 Mar 20;94:81-7. [Epub ahead of print].
34. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurological manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020 Apr 10. [Epub ahead of print].
35. Fang D. SARS: facts and considerations for the orthopaedic community. J Orthop Surg (Hong Kong). 2003 Jun;11(1):3-5.
36. Cherry JD, Krogstad P. SARS: the first pandemic of the 21st century. Pediatr Res. 2004 Jul;56(1):1-5. Epub 2004 May 19.
37. Christian MD, Poutanen SM, Loutfy MR, Muller MP, Low DE. Severe acute respiratory syndrome. Clin Infect Dis. 2004 May 15;38(10):1420-7. Epub 2004 Apr 29.
38. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, Ahuja A, Yung MY, Leung CB, To KF, Lui SF, Szeto CC, Chung S, Sung JJ. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003 May 15;348(20):1986-94. Epub 2003 Apr 7.
39. Lau HMC, Lee EWC, Wong CNC, Ng GYF, Jones AYM, Hui DSC. The impact of severe acute respiratory syndrome on the physical profile and quality of life. Arch Phys Med Rehabil. 2005 Jun;86(6):1134-40.
40. Lau HMC, Ng GYF, Jones AYM, Lee EWC, Siu EHK, Hui DSC. A randomised controlled trial of the effectiveness of an exercise training program in patients recovering from severe acute respiratory syndrome. Aust J Physiother. 2005;51(4):213-9.
41. McCray PB Jr, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, Netland J, Jia HP, Halabi C, Sigmund CD, Meyerholz DK, Kirby P, Look DC, Perlman S. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol. 2007 Jan;81(2):813-21. Epub 2006 Nov 1.
42. Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, Lu Y, Wu D, He L, Yao K. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. 2003 Jul;200(3):282-9.
43. Hsiao CH, Chang MF, Hsueh PR, Su IJ. Immunohistochemical study of severe acute respiratory syndrome-associated coronavirus in tissue sections of patients. J Formos Med Assoc. 2005 Mar;104(3):150-6.
44. Mendias CL, Roche SM, Harning JA, Davis ME, Lynch EB, Sibilsky Enselman ER, Jacobson JA, Claflin DR, Calve S, Bedi A. Reduced muscle fiber force production and disrupted myofibril architecture in patients with chronic rotator cuff tears. J Shoulder Elbow Surg. 2015 Jan;24(1):111-9. Epub 2014 Sep 3.
45. Gumucio JP, Qasawa AH, Ferrara PJ, Malik AN, Funai K, McDonagh B, Mendias CL. Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis. FASEB J. 2019 Jul;33(7):7863-81. Epub 2019 Apr 2.
46. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3. [Epub ahead of print]. Erratum in: Intensive Care Med. 2020 Apr 6.
47. Fu S, Fu X, Song Y, Li M, Pan PH, Tang T, Zhang C, Jiang T, Tan D, Fan X, Sha X, Ma J, Huang Y, Li S, Zheng Y, Qian Z, Xiong Z, Xiao L, Long H, Chen J, Ouyang Y. Virologic and clinical characteristics for prognosis of severe COVID-19: a retrospective observational study in Wuhan, China. 2020 Apr 6. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.04.03.20051763v1
48. Huang Y, Yang R, Xu Y, Gong P. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China. 2020 Mar 5. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.02.27.20029009v2
49. Gallardo E, de Andrés I, Illa I. Cathepsins are upregulated by IFN-gamma/STAT1 in human muscle culture: a possible active factor in dermatomyositis. J Neuropathol Exp Neurol. 2001 Sep;60(9):847-55.
50. Authier FJ, Chazaud B, Plonquet A, Eliezer-Vanerot MC, Poron F, Belec L, Barlovatz-Meimon G, Gherardi RK. Differential expression of the IL-1 system components during in vitro myogenesis: implication of IL-1beta in induction of myogenic cell apoptosis. Cell Death Differ. 1999 Oct;6(10):1012-21.
51. Forcina L, Miano C, Scicchitano BM, Rizzuto E, Berardinelli MG, De Benedetti F, Pelosi L, Musarò A. Increased circulating levels of interleukin-6 affect the redox balance in skeletal muscle. Oxid Med Cell Longev. 2019 Nov 16;2019:3018584.
52. Tang H, Pang S, Wang M, Xiao X, Rong Y, Wang H, Zang YQ. TLR4 activation is required for IL-17-induced multiple tissue inflammation and wasting in mice. J Immunol. 2010 Aug 15;185(4):2563-9. Epub 2010 Jul 14.
53. Reid MB, Li YP. Tumor necrosis factor-alpha and muscle wasting: a cellular perspective. Respir Res. 2001;2(5):269-72. Epub 2001 Jul 12.
54. Layne MD, Farmer SR. Tumor necrosis factor-alpha and basic fibroblast growth factor differentially inhibit the insulin-like growth factor-I induced expression of myogenin in C2C12 myoblasts. Exp Cell Res. 1999 May 25;249(1):177-87.
55. Broussard SR, McCusker RH, Novakofski JE, Strle K, Shen WH, Johnson RW, Dantzer R, Kelley KW. IL-1beta impairs insulin-like growth factor I-induced differentiation and downstream activation signals of the insulin-like growth factor I receptor in myoblasts. J Immunol. 2004 Jun 15;172(12):7713-20.
56. Otis JS, Niccoli S, Hawdon N, Sarvas JL, Frye MA, Chicco AJ, Lees SJ. Pro-inflammatory mediation of myoblast proliferation. PLoS One. 2014 Mar 19;9(3):e92363.
57. Madaro L, Passafaro M, Sala D, Etxaniz U, Lugarini F, Proietti D, Alfonsi MV, Nicoletti C, Gatto S, De Bardi M, Rojas-García R, Giordani L, Marinelli S, Pagliarini V, Sette C, Sacco A, Puri PL. Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat Cell Biol. 2018 Aug;20(8):917-27. Epub 2018 Jul 26.
58. Guo KJ, Zhao FC, Guo Y, Li FL, Zhu L, Zheng W. The influence of age, gender and treatment with steroids on the incidence of osteonecrosis of the femoral head during the management of severe acute respiratory syndrome: a retrospective study. Bone Joint J. 2014 Feb;96-B(2):259-62.
59. Zhao FC, Guo KJ, Li ZR. Osteonecrosis of the femoral head in SARS patients: seven years later. Eur J Orthop Surg Traumatol. 2013 Aug;23(6):671-7. Epub 2012 Jul 13.
60. Webster JM, Fenton CG, Langen R, Hardy RS. Exploring the interface between inflammatory and therapeutic glucocorticoid induced bone and muscle loss. Int J Mol Sci. 2019 Nov 16;20(22):E5768.
61. U.S. Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). Accessed 2020 Apr 27. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
62. Qi D, Yan X, Tang X, Peng J, Yu Q, Feng L, Yuan G, Zhang A, Chen Y, Yuan J, Huang X, Zhang X, Hu P, Song Y, Qian C, Sun Q, Wang D, Tong J, Xiang J. Epidemiological and clinical features of 2019-nCoV acute respiratory disease cases in Chongqing municipality, China: a retrospective, descriptive, multiple-center study. 2020 Mar 3. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.03.01.20029397v1
63. Easom N, Moss P, Barlow G, Samson A, Taynton T, Adams K, Ivan M, Gajee K, Eastick K, Lillie PJ. Sixty-eight consecutive patients assessed for COVID-19 infection: experience from a UK regional infectious disease unit. Influenza Other Respir Viruses. 2020 Mar 29. [Epub ahead of print].
64. Liang Y, Liang J, Zhou Q, Li X, Lin F, Deng Z, Zhang B, Li L, Wang X, Zhu H, Ma Q, Tong X, Xu J, Sun Y. Prevalence and clinical features of 2019 novel coronavirus disease (COVID-19) in the fever clinic of a teaching hospital in Beijing: a single-center, retrospective study. 2020 Feb 28. Accessed 2020 Apr 27. https://www.medrxiv.org/content/10.1101/2020.02.25.20027763v2
65. Lau EMC, Chan FWK, Hui DSC, Wu AKL, Leung PC. Reduced bone mineral density in male severe acute respiratory syndrome (SARS) patients in Hong Kong. Bone. 2005 Sep;37(3):420-4.
66. van Niekerk G, Engelbrecht AM. Inflammation-induced metabolic derangements or adaptation: an immunometabolic perspective. Cytokine Growth Factor Rev. 2018 Oct;43:47-53. Epub 2018 Jun 28.
67. Hong N, Du XK. Avascular necrosis of bone in severe acute respiratory syndrome. Clin Radiol. 2004 Jul;59(7):602-8.
68. Lv H, de Vlas SJ, Liu W, Wang TB, Cao ZY, Li CP, Cao WC, Richardus JH. Avascular osteonecrosis after treatment of SARS: a 3-year longitudinal study. Trop Med Int Health. 2009 Nov;14(Suppl 1):79-84. Epub 2009 Jun 5.
69. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, Pesenti A, Peyvandi F, Tripodi A. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020 Apr 17. [Epub ahead of print].
70. Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost. 2020 Apr 17. [Epub ahead of print].
71. Sun W, Li ZR, Shi ZC, Zhang NF, Zhang YC. Changes in coagulation and fibrinolysis of post-SARS osteonecrosis in a Chinese population. Int Orthop. 2006 Jun;30(3):143-6. Epub 2006 Mar 18.
72. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, De Leacy RA, Shigematsu T, Ladner TR, Yaeger KA, Skliut M, Weinberger J, Dangayach NS, Bederson JB, Tuhrim S, Fifi JT. Large-vessel stroke as a presenting feature of COVID-19 in the young. N Engl J Med. 2020 Apr 28;(April):e60. [Epub ahead of print].
73. Gralinski LE, Ferris MT, Aylor DL, Whitmore AC, Green R, Frieman MB, Deming D, Menachery VD, Miller DR, Buus RJ, Bell TA, Churchill GA, Threadgill DW, Katze MG, McMillan L, Valdar W, Heise MT, Pardo-Manuel de Villena F, Baric RS. Genome wide identification of SARS-CoV susceptibility loci using the collaborative cross. PLoS Genet. 2015 Oct 9;11(10):e1005504.
74. Liu P, Lee S, Knoll J, Rauch A, Ostermay S, Luther J, Malkusch N, Lerner UH, Zaiss MM, Neven M, Wittig R, Rauner M, David JP, Bertolino P, Zhang CX, Tuckermann JP. Loss of menin in osteoblast lineage affects osteocyte-osteoclast crosstalk causing osteoporosis. Cell Death Differ. 2017 Apr;24(4):672-82. Epub 2017 Jan 20.
75. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999 May;103(9):1345-52.
76. Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J, Nanes MS. Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology. 2000 Nov;141(11):3956-64.
77. Grange L, Nguyen MVC, Lardy B, Derouazi M, Campion Y, Trocme C, Paclet MH, Gaudin P, Morel F. NAD(P)H oxidase activity of Nox4 in chondrocytes is both inducible and involved in collagenase expression. Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1485-96.
78. Latourte A, Cherifi C, Maillet J, Ea HK, Bouaziz W, Funck-Brentano T, Cohen-Solal M, Hay E, Richette P. Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis. Ann Rheum Dis. 2017 Apr;76(4):748-55. Epub 2016 Oct 27.
79. Aizawa T, Kon T, Einhorn TA, Gerstenfeld LC. Induction of apoptosis in chondrocytes by tumor necrosis factor-alpha. J Orthop Res. 2001 Sep;19(5):785-96.
80. Zhang K, Asai S, Yu B, Enomoto-Iwamoto M. IL-1β irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro. Biochem Biophys Res Commun. 2015 Aug 7;463(4):667-72. Epub 2015 Jun 4.
81. Millar NL, Akbar M, Campbell AL, Reilly JH, Kerr SC, McLean M, Frleta-Gilchrist M, Fazzi UG, Leach WJ, Rooney BP, Crowe LA, Murrell GA, McInnes IB. IL-17A mediates inflammatory and tissue remodelling events in early human tendinopathy. Sci Rep. 2016 Jun 6;6:27149.
82. Backman LJ, Eriksson DE, Danielson P. Substance P reduces TNF-α-induced apoptosis in human tenocytes through NK-1 receptor stimulation. Br J Sports Med. 2014 Oct;48(19):1414-20. Epub 2013 Aug 30.
83. Gumucio JP, Mendias CL. Atrogin-1, MuRF-1, and sarcopenia. Endocrine. 2013 Feb;43(1):12-21. Epub 2012 Jul 20.
84. Kou K, Momosaki R, Miyazaki S, Wakabayashi H, Shamoto H. Impact of nutrition therapy and rehabilitation on acute and critical illness: a systematic review. J UOEH. 2019;41(3):303-15.
85. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020 Apr 13. [Epub ahead of print].
86. Ceribelli A, Motta F, De Santis M, Ansari AA, Ridgway WM, Gershwin ME, Selmi C. Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy. J Autoimmun. 2020 May;109:102442. Epub 2020 Apr 2.
87. Belopolskaya OB, Smelaya TV, Moroz VV, Golubev AM, Salnikova LE. Clinical associations of host genetic variations in the genes of cytokines in critically ill patients. Clin Exp Immunol. 2015 Jun;180(3):531-41. Epub 2015 Apr 3.