Archive | Basic Science RSS for this section

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.

Surgery to Repair the Hip’s ‘Rotator Cuff’

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.

Symptoms from gluteus medius tendon tears are common in people older than 50 years, but they are hard to distinguish from referred pain due to lumbar spine conditions or hip disorders such as osteoarthritis and femoroacetabular impingement. Because conservative measures are often effective, surgical remedies are not commonly discussed in the literature.

An anatomical study of the gluteus medius tendon found that the posterior part of the tendon has a fan-like shape and converges onto the superoposterior facet of the greater trochanter. The anterolateral part runs posteroinferiorly toward the lateral facet of the greater trochanter. Both the posterior and anterolateral parts insert via fibrocartilage. Given the nonuniform structure of this tendon, the thin anterolateral part may be more prone to tears than the thick posterior part.

In another recent study, a single surgeon described his experience with 185 consecutive gluteus medius tendon tear repairs.1 Tendon changes were confirmed preoperatively on MRI. Roughening of all appropriate surfaces preceded multiple-suture repair through bone holes, with sutures in line with the tendon segment being attached. Of the 185 patients, 165 completed 5- to 10-year phone follow-ups. The average age was 69 and 92% were female. There was no histological evidence of bursitis in any case. Only 9 patients reported worse Oxford Hip Scores at the 5-year follow-up; deep vein thrombotic events occurred in 4% of patients despite prophylaxis. Other common gluteus medius tendon repair techniques include utilization of suture anchors through a mini-open2 or arthroscopic approach.

Unlike degenerative rotator cuff tears of the shoulder, both incomplete and complete acute tears of the gluteus medius respond well to repair surgery. More advanced degenerative gluteus medius tendon changes do not respond as well. It is not clear what the differences are in the mechanical and biochemical mechanisms of rotator cuff and gluteal tendon changes that make surgery to repair the former seemingly less successful than surgery to repair the latter. Nevertheless, these four studies show promise for surgical interventions that have a reasonable chance of being effective, with relatively low risk.

References

  1. Fox OJK, Wertheimer G, Walsh MJ. Primary Open Abductor Reconstruction: A 5 to 10-Year Study. J Arthroplasty. 2020 Apr;35(4):941-944. doi: 10.1016/j.arth.2019.11.012. Epub 2019 Nov 14. PMID: 31813815
  2. Caleb M Gulledge, Eric C Makhni. Open Gluteus Medius and Minimus Repair With Double-Row Technique and Bioinductive Implant Augmentation. Arthrosc Tech 2019 May 17;8(6):e585-e589. doi: 10.1016/j.eats.2019.01.019. eCollection 2019 Jun. PMID: 31334014 PMCID: PMC6620622

Osteoarthritis Progression: Our Current Understanding

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.

Our understating of the progression pathways in knee osteoarthritis (OA) has evolved dramatically in recent years, as described in a recent review article.1 Over the past 2 decades, we have come to view the knee joint as an organ unto itself (with cartilage, synovium, bone, ligaments, and capsule). In the knee, we add to the mix the meniscus, which not only guides motion but is responsible for weight distribution on articular cartilage. Investigations into the etiology and progression of knee OA have merged joint mechanics with insights from studies of inflammation and immunology.

Woodell-May and Sommerfeld examine the process of knee OA as a wound-healing response. Triggered by damage-associated molecular patterns, the innate immune system is typically the first responder to this process. The acute phase in wound healing is short and involves infiltration of neutrophils. In response to neutrophil signals, monocytes migrate from the vessels and differentiate into macrophages, initially type I (inflammatory), which help form the granulation tissue seen in wound healing.

One take-home from the review article is that OA progression may be driven by the chronic inflammation associated with continuing efforts to heal. The back-and-forth between stimulating inflammation (M1 macrophages) and modulating inflammation (M2 macrophages) seems to be predominately driven from the synovium. In addition, specific receptors and intracellular kinases (such as toll-like receptors and mitogen-activated protein kinase) are upregulated in many OA samples.

M1 macrophages promote the elaboration of TNFα and IL-1 by synovial cells. Both cytokines are also active in rheumatoid arthritis (RA). Biologic treatment directed at either one of those cytokines can be effective in RA, but such treatment does not appear to be effective in OA. Over the past decade, the use of autologous conditioned serum (serum drawn off after blood is exposed to glass beads and incubated) has been studied in an attempt to reduce IL-1 activity. The conditioned serum also seems to affect TNFα and has shown some early promise in OA cases.

This burgeoning basic-science knowledge about OA has the potential to lead to disease-modifying treatments, which would revolutionize how orthopaedists approach OA treatment.

Reference
1. Woodell-May JE, Sommerfeld SD. Role of Inflammation and the Immune System in the Progression of Osteoarthritis. J Orthop Res. 2020 Feb;38(2):253-257. doi: 10.1002/jor.24457. Epub 2019 Sep 12. Review. PMID: 31469192

Pulsed EMF Stimulation for Tendon Healing? Stay Tuned

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 effects of electrical currents on early wound healing are well known and studied. The possibility that stimulation of bone formation could be induced with a pulsed electromagnetic field (PEMF) was investigated in the 1960s and translated into clinical use by the 1970s. But the clinical use of PEMF for tendon disorders has not met with similar success.

The precise mechanisms by which these fields affect different tissues is easier to study with the tools we have available today. The measurable parameters of PEMF are intensity, duration, frequency, and duty cycle (percent of time the field is on). Nevertheless, many questions about the possible adverse effects of these fields, their focal delivery, and their possible clinical applications remain unanswered.

In a study of human tendon cells, researchers artificially induced inflammatory cues in cultures using different concentrations of IL‐1β.1 When 1 ng/mL of IL‐1β was used, subsequent cytokine and metalloprotease expression was measured at 1, 2, 3, and 7 days after various PEMF exposures.

The PEMF exposure parameters that most evidently decreased the production of IL-6 and tumor necrosis factor-α (TNF-α) were 4 mT, 5 Hz, and a 50% duty cycle. Those same parameters decreased the expression of TNFα, IL-6, IL-8, COX-2, MMP-1, MMP-2, and MMP-3, while at the same time increasing gene expression of the anti-inflammatory proteins IL-4, IL-10, and TIMP-1. However, the combination of 5 mT and 50% duty cycle had a negative impact on cell viability.

These preliminary results may help guide future investigations, but the authors note that the parameters for optimal PEMF effectiveness on tendon cells may vary with time from insult, further complicating the selection of field parameters.

Reference

  1. Vinhas A, Rodrigues MT, Gonçalves AI, Reis RL, Gomes ME. Pulsed Electromagnetic Field Modulates Tendon Cells Response in IL-1β-Conditioned Environment. J Orthop Res. 2020 Jan;38(1):160-172. doi: 10.1002/jor.24538. Epub 2019 Dec 10.

Shedding Low-Level Laser Light on Knee OA

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.

Low-level laser therapy (LLLT) has been used in multiple countries to treat the pain and function deficits associated with knee osteoarthritis (OA). The wavelength typically used is in the near-infrared region. However, this therapy is not recommended by most clinical guidelines, including those of the Osteoarthritis Research Society International. The hesitancy to recommend LLLT is due largely to conflicting published findings and unresolved dose-related issues such as wavelength, intensity, and frequency of treatment. For treating knee OA, the World Association for Laser Therapy (WALT) recommends applying four times the laser dose with continuous rather than pulsed irradiation.

To try to resolve conflicting evidence, Stausholm et al. conducted a systematic review and meta-analysis of randomized, placebo-controlled trials of LLLT, distilling 22 trials from 2,735 initially identified articles.1 Pain, as measured by a 0 to 100 mm visual analog scale (VAS), was significantly reduced by LLLT compared with placebo at the end of therapy (14.23 mm VAS; 95% CI 7.31 to 21.14) and during follow-ups 1 to 12 weeks later (15.92 mm VAS; 95% CI 6.47 to 25.37). Subgroup analysis revealed that pain was significantly reduced by the recommended LLLT doses compared with placebo at the end of therapy (18.71 mm VAS; 95% CI 9.42 to 27.99) and during follow-ups 2 to 12 weeks after the end of therapy (23.23 mm VAS; 95% CI 10.60 to 35.86).

Pain reduction from the recommended doses peaked during follow-ups 2 to 4 weeks after the end of therapy. Disability was also significantly reduced by LLLT, and no adverse events were reported in any of the studies. Notably, in light of JBJS Editor-in-Chief Marc Swiontkowski’s recent comments about the quality of meta-analyses, this meta-analysis was reported in accordance with PRISMA guidelines and all included trials were evaluated for risk of bias.

What remains unclear is how far past the skin the varied wavelengths and intensities (usually 1 to 8 Joules) of laser energy penetrate. Likewise, tissue heating has not been measured or analyzed. Still, at present, it appears that LLLT used with WALT guidelines is a safe and potentially effective treatment for the pain and dysfunction of knee OA.

Reference

  1. Stausholm MB, Naterstad IF Msc, Joensen J, Lopes-Martins RÁB, Sæbø H Msc, Lund H, Fersum KV, Bjordal JM. Efficacy of low-level laser therapy on pain and disability in knee osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open. 2019 Oct 28;9(10):e031142. doi: 10.1136/bmjopen-2019-031142. PMID: 31662383

What’s New in Musculoskeletal Basic Science 2019

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 summaries. This month, co-author Philipp B. Leucht, MD selected the most clinically compelling findings from the 40 studies summarized in the December 4, 2019 “What’s New in Musculoskeletal Basic Science.

Muscle Regeneration
–Recent findings about the cellular players in muscle regeneration may allow further development of clinical treatment options for patients with muscle sprains, tears, and loss. Toward that end, Wosczyna et al. established the crucial role of fibroadipogenic progenitors (FAPs, also called mesenchymal stromal cells) in muscle repair and maintenance.1 Using a mouse model, the researchers showed that FAPs are necessary for muscle regeneration by supporting muscle stem cells.

Bone-Brain Crosstalk
–The bone-derived hormone osteocalcin supports development of the musculoskeletal system and the brain. Osteocalcin can regulate anxiety and cognition in adult mice, and Obri et al. postulated that declining levels of osteocalcin may be responsible for the cognitive decline seen in aging.2 This finding may spur investigations into exogenous treatment with osteocalcin to restore brain function.

Tendon Regeneration
–Tendon cells express the transcription factor Scleraxis, which has facilitated the identification of the tendon stem progenitor cell (TSPC). Best and Loiselle identified a Scleraxis-positive cell population in the bridging scar tissue after tendon injury.3 These findings suggest that TSPCs are present in the adult tendon and contribute to the healing response; however, their small number does not result in successful tendon regeneration, but rather in scar formation with interspersed tendon tissue.

–Abraham et al. identified the upregulation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and its downstream targets in tendinopathy-affected human rotator cuff tendons.4 Using a transgenic mouse model in which IKKß (inhibitor of nuclear factor kappa-B kinase subunit beta), a key regulator of inflammation, was overexpressed, they demonstrated the development of tendinopathy in mouse rotator cuff tendons. The deletion of IKKß had a protective effect from chronic overuse.

Bone Regeneration
–Successful bone healing after fracture is highly dependent on the presence and activation of skeletal stem cells. Chan et al. precisely defined the human skeletal stem cell (hSSC), demonstrated the hSSC’s role in human fracture repair, and provided evidence that these cells generate a bone marrow-supportive niche.5 These cells also give rise to bone, cartilage, and stromal progenitor cells.

References

  1. Wosczyna MN, Konishi CT, Perez Carbajal EE, Wang TT, Walsh RA, Gan Q, Wagner MW, Rando TA. Mesenchymal stromal cells are required for regeneration and homeostatic maintenance of skeletal muscle. Cell Rep.2019 May 14;27(7):2029-2035.e5.
  2. Obri A, Khrimian L, Karsenty G, Oury F. Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nat Rev Endocrinol.2018 Mar;14(3):174-82. Epub 2018 Jan 29.
  3. Best KT, Loiselle AE. Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells. FASEB J.2019 Jul;33(7):8578-87. Epub 2019 Apr 5.
  4. Abraham AC, Shah SA, Golman M, Song L, Li X, Kurtaliaj I, Akbar M, Millar NL, Abu-Amer Y, Galatz LM, Thomopoulos S. Targeting the NF-κB signaling pathway in chronic tendon disease. Sci Transl Med.2019 Feb 27;11(481):eaav4319.
  5. Chan CKF, Gulati GS, Sinha R, Tompkins JV, Lopez M, Carter AC, Ransom RC, Reinisch A, Wearda T, Murphy M, Brewer RE, Koepke LS, Marecic O, Manjunath A, Seo EY, Leavitt T, Lu WJ, Nguyen A, Conley SD, Salhotra A, Ambrosi TH, Borrelli MR, Siebel T, Chan K, Schallmoser K, Seita J, Sahoo D, Goodnough H, Bishop J, Gardner M, Majeti R, Wan DC, Goodman S, Weissman IL, Chang HY, Longaker MT. Identification of the human skeletal stem cell. 2018; Sep 20;175(1):43-56.e21.