Tag Archive | inflammation

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.

Autophagy: A Culprit in Aseptic Implant Loosening?

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. 

Periprosthetic membranes are fibrous granulomatous tissues composed of wear debris and numerous cell types, including fibroblasts, macrophages, osteoclasts (OCs), osteoblasts (OBs), osteocytes (OSTs), mesenchymal stem cells (MSCs), synovial cells, endothelial cells, and, rarely, lymphocytes. Macrophages ingest wear debris, resulting in the production of proinflammatory factors such as tumor necrosis factor (TNF); interleukin (IL)-1, IL-6, IL-17; macrophage colony-stimulating factor (M-CSF); and reactive oxygen species. In addition, macrophages can differentiate into OCs, which can induce the fibroblast cytokines that contribute to bone resorption.

Autophagy is the basic catabolic mechanism that degrades/recycles unnecessary or dysfunctional cellular components through the action of lysosomes. The breakdown of cellular components promotes cellular survival during stress, such as starvation, by maintaining cellular energy levels. In most instances, autophagy does not lead to cell death. Although the products of autophagy are typically recycled intracellularly, they may also be secreted.

Autophagy is also important for the differentiation of OBs, OSTs, and OCs. In addition, autophagy is involved in OB mineralization, and autophagy proteins are required for OC bone resorption. Autophagy appears to be triggered by wear debris in OCs, OBs, and macrophages, where the process promotes the secretion of proinflammatory proteins associated with the development of aseptic loosening. Autophagy can also be involved in the secretion of proteins such as chemokine (C-C motif) ligand 2 (CCL2) and leukemia inhibitory factor (LIF), which were both overexpressed in aseptic loosening in a rat model.

Autophagy inhibition has been shown to decrease osteolysis severity in animal models. For example, 3-methyladenine inhibition of the autophagy response to TiAl6V4 particles improved bone microarchitecture in a murine calvaria resorption model. Although autophagy will probably not be the final answer for prosthetic loosening, it is an avenue that should prompt future research into new therapeutic approaches.

Reference
Camuzard O, Breuil V, Carle GF, Pierrefite-Carle V. Autophagy Involvement in Aseptic Loosening of Arthroplasty Components. J Bone Joint Surg Am. 2019 Mar 6;101(5):466-472. doi: 10.2106/JBJS.18.00479. PMID: 30845042

 

June 2018 Article Exchange with JOSPT

jospt_article_exchange_logo1In 2015, JBJS launched an “article exchange” collaboration with the Journal of Orthopaedic & Sports Physical Therapy (JOSPT) to support multidisciplinary integration, continuity of care, and excellent patient outcomes in orthopaedics and sports medicine.

During the month of June 2018, JBJS and OrthoBuzz readers will have open access to the JOSPT article titled “Physical Activity and Exercise Therapy Benefit More Than Just Symptoms and Impairments in People With Hip and Knee Osteoarthritis.”

The authors issue a clear “call to action” for exercise therapy in patients with hip and knee osteoarthritis (OA), not only because it reduces arthritis symptoms, but also because physical activity helps prevent at least 35 chronic conditions and helps treat at least 26 chronic conditions.

What Really Causes Shoulder Tendinitis Pain?

Calcific tendinitis in the shoulder can be a perplexing problem for orthopaedists and patients. While it’s a painless, asymptomatic condition in some people, for others it’s extremely painful and impairs range of motion and shoulder function.

In the February 3, 2016 edition of The Journal of Bone & Joint Surgery, a prospective cohort observational study by Hackett et al. helps explain why that might be. After immunohistochemically evaluating biopsied tendon samples from three groups of patients (ten with painful calcific tendinitis, ten undergoing rotF2.mediumator cuff repair, and ten “controls” undergoing a surgical stabilization procedure), the authors found a twofold to eightfold increase of nerve markers, neovascularization, macrophages, M2 macrophages, and mast cells in the calcific tendinitis group compared with the two other groups. The authors conclude that these findings “are consistent with the hypothesis that, in calcific tendinitis, the calcific material is inducing a vigorous inflammatory response within the tendon with formation of new blood vessels and nerves.”

In an insightful commentary on the study, Scott Rodeo cites the study’s main limitation—that biopsy specimens from patients with asymptomatic calcific tendinitis were not studied. That leads the commentator to ask what triggers the transition from asymptomatic lesion to an acutely painful one—and to review some of the current explanatory theories. One posits that osteoclasts drawn to the lesion activate resorption of the calcium. Active resorption causes pain, the theory goes, and that’s when patients frequently receive subacromial steroid injections. Dr. Rodeo suggests that subsequent pain relief may arise more from the natural completion of the resorption process than from the treatment.

Dr. Rodeo further discusses the possibility that active cell-mediated calcium resorption might be a response to microscopic tendon injury in the area of the calcific deposit. He also summarizes interesting stem cell-based theories on what might initiate the deposition of calcium crystals in the first place.

Patient Pain Perception: Two New Studies

The connection between patient pain and clinical orthopaedic outcomes has received much attention lately. Here are relevant findings from two recent studies:

–An in-press study of 48 patients (average age of 72 years) who underwent TKA found that those with low pain thresholds prior to surgery (as measured with VAS scores while a blood-pressure cuff was inflated over the proximal forearm) were more likely to have lower Knee Society pain and function scores two years after surgery than those with moderate or high pain thresholds. The authors use this test in preoperative workups, and they advise patients who grade the cuff stimulus as severe that “their clinical outcomes are expected to be inferior to [those of] other patients,” encouraging such patients to take that into account before consenting to surgery.

–Among more than 1,100 patients (average age of 67 years) who participated in the Multicenter Osteoarthritis Study (MOST), inflammation, as evidenced by synovitis and effusion, was associated with reduced pain thresholds. However, resolution of established inflammation did not deliver a significant change in pain thresholds over two years, leading the authors to conclude that “early targeting of inflammation is a reasonable strategy to test for prevention of sensitization and…reduction of pain severity.”