Archive | Basic Science RSS for this section

Knee OA: Does It Start with Stiff Menisci or Soft Cartilage?

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

As an orthopaedic surgeon, I often noticed the rigidity of the meniscus as I excised it during a total knee replacement. Focused on the job at hand, however, I never closely considered the involvement of menisci in degenerative joint disease. But German researchers recently hypothesized that early biomechanical changes in meniscal tissue occur before articular cartilage changes in knee osteoarthritis.1

To test their hypothesis, they dissected 12 cadaver knees with Kellgren-Lawrence (KL) scores between 1 and 2 and 12 knees with KL scores between 3 and 4. The menisci were carefully embedded in a cast of polymethylmethacrylate using bony attachments to hold the specimens for Einst testing at the anterior horn, pars intermedia, and posterior horn. (Instantaneous modulus of elasticity [Einst] is the measure of the initial response of a viscoelastic material to an initial load before long-term deformity occurs.)  The exposed tibial surface was then cut 10 mm below the joint for Einst testing at the same zones, and the researchers also measured the articular cartilage-to-cartilage contact area.

Mann-Whitney U-testing revealed higher meniscal Einst values with increasing degeneration for both lateral and medial menisci, while the underlying tibial articular cartilage showed a decrease in Einst in the medial compartment. These findings suggest that knee joint degeneration might very well begin with a stiffening of the menisci, followed by articular cartilage softening.

The wide variation in Einst values uncovered in this study leaves open the possibility there is more than one pathway by which the biochemical response to meniscal cytokine expression would lead to subsequent articular cartilage breakdown. Nevertheless, the authors suggest that their findings might prompt the treatment and diagnostic paradigms of knee osteoarthritis to change, “focusing on the degeneration detection of the menisci instead of the articular cartilage.”

Reference 

  1. Seitz AM, Osthaus F, Ignatius A, Dürselen L. Degeneration alters first the biomechanical properties of human menisci before affecting the tibial cartilage. ORS 2020 Annual Meeting Paper No.0687

What’s New in Musculoskeletal Basic Science 2020

Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all such OrthoBuzz specialty-update summaries.

This month, co-author Philipp Leucht, MD selected the most compelling findings from the 15 studies summarized in the December 2, 2020 “What’s New in Musculoskeletal Basic Science.”

Spine: Annulus Fibrosus Findings
The relatively high prevalence of repeat discectomies has caused researchers to focus on characteristics of the annulus fibrosus, the healing of which often remains incomplete after disc herniation.

–Knowing that the neonatal annulus fibrosus shows regenerative capacity, researchers recently identified Scleraxis-lineage cells as the main contributors to those regenerative properties.1 They discovered that the neonatal cellular programming that results in complete functional restoration of the annulus fibrosus is completely absent in the adult annulus fibrosus after injury. Knowledge of this regenerative mechanism could help scientists develop new treatments for annulus fibrosus regeneration in adults.

–Related research demonstrated that the residual strain of the healthy nucleus pulposus generates pre-strain in the outer annulus fibrosus, and that the loss of residual strain, as seen in disc herniation, results in short-term apoptosis and the emergence of a fibrotic cell phenotype in the annulus fibrosus.2 Blocking cell contractility pathways may therefore offer a viable target to prevent post-injury fibrosis.

Spine: Somitogenesis
–The somitogenesis process in vertebrate development is believed to be controlled by an oscillating genetic “clock.” Researchers developed an in vitro modeling system to recapitulate the human segmentation clock,3 determining that the clock causes a new somite to be formed every 5 hours. This model allowed investigators to assess the function of mutations involved in segmentation defects such as congenital spondylocostal dysostosis. This easily manipulated model could provide the framework for discoveries of the gene oscillations and molecular underpinnings in both normal and abnormal vertebral development.

Osteoarthritis
–Transforming growth factor beta (TGF-β) signaling has been revealing in studying osteoarthritis. Researchers found that mice lacking  in Prx1 osteochondral progenitors during development showed joint developmental defects.4 They further found that both postnatal ablation of Tgfbr2 in osteochondral progenitors and pharmacological inhibition of TGF-β receptor 2 led to an osteoarthritis phenotype with accompanied upregulation of the receptor antagonist IL-36α. They then discovered that an IL-36Ra intra-articular injection attenuates osteoarthritis progression in both Tgfbr2-deletion and posttraumatic arthritis models, confirming the IL-36 family as a viable target in fighting osteoarthritis.

Bone Regeneration
–Skeletal stem and progenitor cells migrate to sites of damage after an injury to participate in the repair process. Researchers recently discovered that the quiescent CXCL12-expressing perisinusoidal bone marrow stromal cells also participate in the repair process5 by converting into a skeletal stem-cell-like state after injury. These CCXL12-positive cells are highly malleable and long-living and thus represent an ideal source for bone tissue regeneration.

References

  1. Torre OM, Mroz V, Benitez ARM, Huang AH, Iatridis JC. Neonatal annulus fibrosus regeneration occurs via recruitment and proliferation of Scleraxis-lineage cells. NPJ Regen Med.2019 Dec 20;4:23.
  2. Bonnevie ED, Gullbrand SE, Ashinsky BG, Tsinman TK, Elliott DM, Chao PG, Smith HE, Mauck RL. Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss. Nat Biomed Eng.2019 Dec;3(12):998-1008. Epub 2019 Oct 14.
  3. Matsuda M, Yamanaka Y, Uemura M, Osawa M, Saito MK, Nagahashi A, Nishio M, Guo L, Ikegawa S, Sakurai S, Kihara S, Maurissen TL, Nakamura M, Matsumoto T, Yoshitomi H, Ikeya M, Kawakami N, Yamamoto T, Woltjen K, Ebisuya M, Toguchida J, Alev C. Recapitulating the human segmentation clock with pluripotent stem cells. 2020 Apr;580(7801):124-9. Epub 2020 Apr 1.
  4. Li T, Chubinskaya S, Esposito A, Jin X, Tagliafierro L, Loeser R, Hakimiyan AA, Longobardi L, Ozkan H, Spagnoli A. TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Sci Transl Med.2019 May 8;11(491):eaan2585.
  5. Matsushita Y, Nagata M, Kozloff KM, Welch JD, Mizuhashi K, Tokavanich N, Hallett SA, Link DC, Nagasawa T, Ono W, Ono N. A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. Nat Commun.2020 Jan 16;11(1):332.

How Much Radiation Does a Surgeon’s Brain Receive during Femoral Nailing?

OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Impact Science, in response to a recent article in JBJS.

Surgeon exposure to ionizing radiation during C-arm fluoroscopy is common during many orthopaedic procedures, including fracture reduction and fixation-implant positioning. With increased exposure, concern about potential health risks to staff also increases.

A new study in the November 18, 2020 issue of The Journal of Bone & Joint Surgery estimates how much radiation a surgeon’s brain is exposed to while performing short cephalomedullary (SC) nailing over a 40-year career. Ramoutar et al. used two cadaveric specimens (one representing the patient and one head-and-neck specimen representing the surgeon) during a simulated fluoroscopic-guided femoral-nailing procedure.

The dose of radiation to the brain was measured with sensors implanted in the cadaver brain and placed superficially on the skull. Measurements were made with the surgeon specimen set up with different configurations of personal protective equipment (PPE) to test their effectiveness at shielding the brain from radiation.

Ramoutar et al. calculated that the overall extrapolated lifetime dose over 40 working years for surgeons performing 16 SC nailing cases per year without PPE was 2,146 µGy, which is comparable to the radiation exposure during a 1-way flight from London to New York. The authors also found that the use of a thyroid shield was very effective in reducing the radiation exposure to the brain, although the use of additional PPE (e.g., leaded glasses and lead cap) did not add any significant reduction in brain exposure to radiation.

In addition to concluding that the lifetime brain dose of radiation from SC nailing is low, the authors say the findings should encourage surgeons performing this procedure to use thyroid shields. This study also provides a repeatable methodology for future studies investigating brain-radiation doses during other common orthopaedic procedures.

Impact Science is a team of highly specialized subject-area experts (Life Sciences, Physical Sciences, Medicine & Humanities), who collaborate with authors, societies, libraries, universities, and various other stakeholders for services to enhance research impact. Through research engagement and science communication, Impact Science aims at democratizing science by making research-backed content accessible to the world.

 

Balancing Antibiotic Perfusion and Tourniquet Usage

Antibiotics are an integral part of infection prophylaxis in orthopaedic surgery, and tourniquets are widely used during many of those same surgeries. The timing of antibiotic administration in relation to tourniquet use has long been debated. Hanberg et al. explore this “balancing act” in the November 4, 2020 issue of The Journal in a carefully performed animal study.

The researchers anesthetized 24 female pigs and surgically exposed both of their hind calcanei. They then placed microdialysis catheters through drill holes in each calcaneus and also into the subcutaneous adipose tissue in the hind feet. Tourniquets were applied to one hind leg on each animal, and each pig was then randomized into 1 of 3 groups, based on when the animal received 1.5 gm of cefuroxime intravenously:

  • Group A –15 minutes prior to tourniquet inflation
  • Group B – 45 minutes prior to tourniquet inflation
  • Group C – At the time of tourniquet release

Hanberg et al. inflated the tourniquets for 90 minutes in all 3 groups, and then they measured the concentrations of cefuroxime and ischemic markers at regular intervals between the time of tourniquet inflation and up to 480 minutes afterward.

The authors found that in both Groups A and B, cefuroxime concentrations were maintained above the minimum inhibitory concentration (MIC) for Staphylococcus aureus in cancellous bone and adipose tissue throughout the 90 minutes of tourniquet inflation. In addition, injecting cefuroxime at the time of tourniquet deflation (Group C) kept the tissue-antibiotic levels above the MIC on the tourniquet side for 3.5 hours after tourniquet release.

There were no differences in the time above MIC in bone or adipose tissue between the 3 groups, but the researchers noted a trend toward shorter time above MIC in bone in Group A vs. Group C (p=0.08). There was also a tendency toward higher time above MIC in bone on the tourniquet side compared to no-tourniquet side in Group B (p=0.08) and Group C (p=0.06). The researchers also found that, in all the animals, tissue ischemia persisted for 2.5 hours after tourniquet deflation in bone, while the adipose tissue recovered immediately.

This animal study provides useful data and prompts us to ponder ideas for further investigation regarding the interplay between tourniquets and antibiotic perfusion. For example, I think the prolonged ischemia in cancellous bone is a topic that warrants further investigation, and I am also curious whether adding antibiotics at the time of tourniquet release might help combat the potentially negative effects of that ischemia.

Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media

Seeking Molecular Signatures of Ectopic Bone Formation

OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Impact Science, in response to an article in the November 4, 2020 JBJS.

Among military personnel who sustain blast-related injuries, physicians have observed a dramatic increase in the incidence of heterotopic ossification (HO), a pathology in which bone grows abnormally within soft tissues. This condition is frequently observed in association with burns and nonmilitary orthopaedic trauma, and combat-related HO is now occurring at an exceptionally high frequency of approximately 60%.

HO can range from an asymptomatic, incidental finding to a debilitating condition causing chronic pain and impaired movement. Although symptomatic HO is usually treated with surgical excision, identifying HO early in its development could go a long way toward improving quality of life for those with combat injuries.

Previous studies have suggested that certain microRNAs (miRNAs) play an important role in the formation of post-traumatic HO. A group of US researchers recently hypothesized that specific miRNA “signatures” might be present in the tissues of military personnel soon after a blast injury.

The authors collected 10 tissue samples from injured servicemembers during the surgical debridement of their wounds, about 8 days after the initial injuries occurred. The miRNA profiling of the samples, performed using a real-time polymerase chain reaction array, revealed that the tissues from patients who developed HO had upregulated levels of 6 miRNAs previously thought to take part in various bone-formation processes. Moreover, when some of those miRNAs were introduced into cultures of mesenchymal progenitor cells, the researchers found that 2 specific miRNAs (miR-1 and miR-206) were the most robust osteogenic “enhancers.” Interestingly, those same 2 miRNAs were found to target the downstream transcription factor SOX9, a deficiency of which can lead to a skeletal malformation syndrome.

These findings show that there are indeed early molecular signatures in the tissues of patients whose injuries progress to HO. While these novel insights into the molecular mechanisms underlying the development of HO may open doors to new therapeutic possibilities, Takamitsu Maruyama, PhD, in a commentary on the findings, cautions that modulating miR-1 and miR-206 “could affect not only HO formation but also the bone-healing process.”

Impact Science is a team of highly specialized subject-area experts (Life Sciences, Physical Sciences, Medicine & Humanities) who collaborate with authors, societies, libraries, universities, and various other stakeholders for services to enhance research impact. Through research engagement and science communication, Impact Science aims at democratizing science by making research-backed content accessible to the world.

A Genetic Basis for Adhesive Capsulitis?

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

Adhesive capsulitis (AC), colloquially known as frozen shoulder, is associated with conditions such as diabetes, cardiopulmonary disorders, stroke, Parkinsonism, and injury. However, many cases are idiopathic. Given the inflammatory nature of the condition, clinicians often administer intra-articular steroid injections in recalcitrant cases where physical therapy alone is too painful or nonproductive. Some cases, particularly in patients with diabetes, may require manipulation, brisement, or arthroscopic release.

To better understand the genetic basis of AC, investigators obtained punch tissue samples from the middle glenohumeral ligament and rotator cuff interval from AC patients undergoing arthroscopic release surgery (mean age of 53 years) and from a comparative group of patients undergoing arthroscopic surgery for shoulder instability (mean age of 24 years).1 The researchers performed RNA sequencing-based transcriptomics on the samples and, after identifying differentially expressed genes, they applied real-time reverse transcription polymerase chain reaction (RT-PCR) to obtain more detailed genetic data.

A total of 545 genes were differentially expressed. The top 50 were associated with extracellular matrix remodeling. Patient age and sex did not have a major influence on gene expression. The genes marked by overexpression (not necessarily protein expression) were genes for matrix metallopeptidase 13 and platelet-derived growth factor subunit B. Other suspects included the gene for metalloprotease 9 and COL18A1.

In the discussion, the authors comment on the association between AC and protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK). FAK activation is particularly sensitive to fibronectin and other integrins. Activated FAK also controls cell migration and focal adhesion assembly. These interesting associations may also shine light onto the etiology of other musculoskeletal diseases.

Reference

  1. Kamal N, McGee SL, Eng K, Brown G, Beattie S, Collier F, Gill S, Page RS.
    Transcriptomic analysis of adhesive capsulitis of the shoulder.
    J Orthop Res. 2020 Oct;38(10):2280-2289. doi: 10.1002/jor.24686. Epub 2020 Apr 17. PMID: 32270543

The Importance of a “Well-Rounded” Hip

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

Fifty years ago, the precise etiology of hip osteoarthritis (OA) was not clear. In 1976, Solomon proposed 3 potential causes of osteoarthritis in general:1

  1. Failure of essentially normal cartilage subjected to abnormal or incongruous loading for long periods
  2. Damaged or defective cartilage failing under normal conditions of loading
  3. Breakup of articular cartilage due to defective subchondral bone

In 1986, Harris expanded on this concept by noting that mild acetabular dysplasia and/or pistol grip deformity were associated with 90% of patients who had “so-called primary or idiopathic” hip OA.2 Harris further claimed that “when these abnormalities are taken in conjunction with the detection of other metabolic abnormalities that can lead to osteoarthritis of the hip,…it seems clear that either osteoarthritis of the hip does not exist at all as a primary disease entity or, if it does, is extraordinarily rare.”

Subsequently, acetabular dysplasia was defined as an acetabular shape where the lateral center edge angle (LCEA) was <25°, and the cam and pincer deformities were introduced as forms of acetabular dysplasia. Acetabular retroversion, as detected by the crossover sign seen in anterolateral hip radiographs, was recognized later, and Tonnis used CT imaging to determine acetabular and femoral anteversion.3

In 2020, investigators suspected that zonal-acetabular radius of curvature (ZARC) might play a role in hip-joint shape disorders.4 ZARC is the radius of curvature of the articular contact surface (from the margin of the fovea centralis to the acetabular rim), and the authors analyzed ZARC in anterior, superior, and posterior zones in subjects with normal, borderline, and dysplastic hips. (“Normal” was defined as LCEA of 25° to <40°; “borderline” as LCEA of 20° to <25°; and “dysplastic” as LCEA of <20°.) The 3-zone ZARC findings are summarized in the table below.

Mean Zonal-Acetabular Radius of Curvature (ZARC)

ZARC Zone Borderline Normal Dysplasia
Anterior 29.8 +/- 2.6 mm 28.0 +/- 2.2 mm 31.5 +/- 2.7 mm *
Superior 25.7 +/- 3.0 mm 25.9 +/- 2.2 mm 25.8 +/- 2.5 mm
Posterior 27.2 +/- 2.5 mm 26.4 +/- 1.9 mm 30.4 +/- 3.3 mm *

* P < 0.01

In this study, the severity of lateral undercoverage affected the anterior and/or posterior zonal-acetabular curvature. The take home message is that, absent metabolic abnormalities, acetabular and femoral head congruity and orientation are the driving forces in hip OA.

References

  1. Solomon L. Patterns of osteoarthritis of the hip. J Bone Joint Surg Br. 1976;58(2):176-83. Epub 1976/05/01. PubMed PMID: 932079.
  2. Harris WH. Etiology of osteoarthritis of the hip. Clinical orthopaedics and related research. 1986(213):20-33. Epub 1986/12/01. PubMed PMID: 3780093.
  3. Tonnis D, Heinecke A. Acetabular and femoral anteversion: relationship with osteoarthritis of the hip. J Bone Joint Surg Am. 1999;81(12):1747-70. Epub 1999/12/23. PubMed PMID: 10608388.
  4. Irie T, Espinoza Orias AA, Irie TY, Nho SJ, Takahashi D, Iwasaki N, et al. Three-dimensional hip joint congruity evaluation of the borderline dysplasia: Zonal-acetabular radius of curvature. J Orthop Res. 2020;38(10):2197-205. Epub 2020/02/20. doi: 10.1002/jor.24631. PubMed PMID: 32073168.

Nontraumatic Osteonecrosis: An Early Target for Gene Therapy

As osteonecrosis of the femoral head (ONFH) progresses, it can impair a patient’s ability to walk, and hip arthroplasty is often the only effective long-term option. Other interventions to relieve the pain of ONFH include surgical decompression of the femoral head, which is generally effective but often does not change the natural history of the process. Once the femoral head collapses and loses sphericity, degenerative arthritis of the hip follows quickly. Well-documented risk factors for ONFH include excessive alcohol consumption and corticosteroid use. But why do some patients with these risk factors develop osteonecrosis, while others do not.

In the September 16, 2020 issue of The Journal, Zhang et al. address that clinical quandary with a genomewide association study on a chart-reviewed cohort of 118 patients with ONFH and >56,000 controls. The findings shed light on what is obviously a condition with multifactorial etiology and complex gene-environment interactions. The case-control study identified 1 gene (PPARGC1B) and 4 single nucleotide variants associated with ONFH overall, and with 2 subgroups—those exposed to corticosteroids and those with femoral head collapse. Steroid intake was highly prevalent in both cohorts—90.7% of the ONFH patients had at least one 3-week course of corticosteroids, compared with 68.3% of controls.

For readers interested in the detailed genetic bases for osteonecrosis, this study offers a treasure trove of data. But for all of us, these findings, after they are verified in other populations, may very well form the basis for pharmacologic and gene-modifying strategies in patients at risk for ONFH. Moreover, osteonecrosis of the femoral head is just one of many musculoskeletal conditions that can probably be addressed with this type of genome-based research strategy.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

Hydrogel + Stem Cells Improve Disc Conditions in Goats

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

One of the key changes leading to intervertebral disc degeneration is the loss of complex proteoglycans in the nucleus pulposus (NP), which leads to a loss of water avidity, physiologic dysfunction, NP tissue rigidity, and disruption of surrounding disc tissues. In humans, these changes can begin as early as the second decade of life. One of the difficulties in developing cellular therapies to address these changes is creating a hydrogel that can support effective delivery of mesenchymal stem cells (MSCs).

University of Pennsylvania researchers chemically induced degeneration in lumbar discs in adult male goats. After 12 weeks, some of the degenerating discs were injected with either a hydrogel alone (n=9 discs) or hydrogel with 10 million mesenchymal stem cells per ml (n=10 discs). The remaining discs received neither injection. Two weeks later, researchers analyzed disc height, hydrogel distribution, and MSC localization using green fluorescent protein (GFP) immunostaining.

After 12 weeks of disc degeneration, disc height was approximately 66% of pre-intervention levels. After 2 weeks of the treatment phase, researchers found an insignificant increase in height in the hydrogel-alone discs, and a significant 7.6% height increase in the hydrogel-with-MSCs discs. Imaging revealed that the majority of hydrogel was located in the NPs of the treated discs.

Treated discs exhibited improved overall histological grade compared to untreated discs, but the improvement was significant only in discs treated with hydrogel + MSCs. The fact that GFP-positive MSCs were identified both in the hydrogel itself and in the surrounding NP tissue suggests that MSCs migrated beyond the injection site.

The question remains whether we can similarly improve physiology in the wide spectrum of degenerative disc disease experienced by humans. Let’s hope that future investigations yield positive findings.

COVID-19’s Musculoskeletal Manifestations

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

The SARS-CoV-2 coronavirus that causes COVID-19 induces the expression of several cytokines and signaling molecules. The impact of these inflammatory mediators on the lungs is the most lethal effect and thus has drawn the most attention. However, COVID-19 can have potentially longer-lasting (but less deadly) musculoskeletal effects.

COVID-19 has not been affecting people long enough to study its effects completely, but we do know that the virus predominantly infects type-II pneumocytes that line the respiratory epithelium. These cells express angiotensin converting enzyme-2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2). Disser et al. note that TMPRSS2 is also expressed in muscle tissue, while only smooth muscle cells and pericytes express ACE2. They add that either ACE2 or TMPRSS2 is expressed in cartilage, menisci, bone, and synovium.

Myalgia has been reported to occur in COVID-19 patients 25% to 50% of the time. The effect on muscle can be severe, with more seriously ill patients having higher levels of creatine kinase. After recovery, patients often show decreased strength and endurance, but it is not clear how much of that is due to deconditioning or to persisting muscle effects. Although arthralgia can also occur, it is hard to separate those symptoms from myalgia, and both may exist at the same time.

Examination of muscle specimens from autopsies of COVID-19 patients shows significant muscle destruction. It is not clear whether the osteoporosis and osteonecrosis sometimes seen with SARS-CoV-2 is due to the virus’s direct effect on bone or to the steroids used to treat patients with more severe cases.

Because it is probable that inflammation associated with cytokine release has an impact on musculoskeletal tissues, orthopaedic surgeons are likely to be faced with a variety of musculoskeletal symptoms in post COVID-19 patients. Preliminary data suggest that rehabilitation for both strength and endurance is effective among patients who recover from COVID-19, but it is not clear whether return to former conditioning levels occurs. The use of immunotherapies, such as IL-1 and IL-6 inhibitors, may have a positive impact on initial treatment in these patients.