A 17-yr-old male lacrosse player on isotretinoin for acne presented to an outpatient clinic with 1 year of insidious onset bilateral anteromedial knee pain. After the summer off with improved pain, his pain resumed with an average exercise load during fall training. He continued to play despite symptoms. Pain was sharp, exacerbated with activity, and improved with rest. He denied trauma, swelling, locking, or weakness. On examination, the patient had a body mass index of 25.61 kg/m 2 . There was no effusion or skin changes. He had mild tenderness to palpation at the left medial patellar facet only. Range of motion, sensation, reflexes, and motor examinations were normal. Ligamentous and meniscal examination maneuvers were negative. There was dynamic valgus with single-leg squat bilaterally. He could single-leg hop without increased pain. He began physical therapy for a presumed diagnosis of patellofemoral pain but symptoms progressed. X-rays of the bilateral knees were normal. Magnetic resonance imaging (MRI) revealed multifocal bone stress injuries in the left distal femur (Fredericson Grade [FG] 4a), proximal tibia [FG 4b] and fibula [FG 3], and right distal femur [FG 4a] and proximal fibula [FG 3]; (Figs. 1, 2). 1,2 Laboratory work was significant for vitamin D insufficiency and appropriately low parathyroid hormone in the setting of calcium supplementation. Dual-energy x-ray absorptiometry and bone scan were age appropriate.The patient began calcium and vitamin D supplementation. Isotretinoin was incidentally discontinued given improved acne. This occurred a few weeks before his MRI evaluation. He was nonweight bearing for 8 wks with symptom improvement and initiation of a progressive therapy protocol. Repeat MRI was obtained at 6 mos given increase in pain with a return to running program. It showed significantly improved bone edema and no new findings. He returned to a low-impact physical therapy protocol with progressive return to sport.

Extracellular vesicles (EVs) have been suggested to transmit the health-promoting effects of exercise throughout the body. Yet, the mechanisms by which beneficial information is transmitted from extracellular vesicles to recipient cells are poorly understood, precluding a holistic understanding of how exercise promotes cellular and tissue health. In this study, using articular cartilage as a model, we introduced a network medicine paradigm to simulate how exercise facilitates communication between circulating EVs and chondrocytes, the cells resident in articular cartilage. Using the archived small RNA-seq data of EV before and after aerobic exercise, microRNA regulatory network analysis based on network propagation inferred that circulating EVs activated by aerobic exercise perturb chondrocyte-matrix interactions and downstream cellular aging processes. Building on the mechanistic framework identified through computational analyses, follow up experimental studies interrogated the direct influence of exercise on EV-mediated chondrocyte-matrix interactions. We found that pathogenic matrix signaling in chondrocytes was abrogated in the presence of exercise-primed EVs, restoring a more youthful phenotype, as determined by chondrocyte morphological profiling and evaluation of chondrogenicity. Epigenetic reprograming of the gene encoding the longevity protein, α-Klotho, mediated these effects. These studies provide mechanistic evidence that exercise transduces rejuvenation signals to circulating EVs, endowing EVs with the capacity to ameliorate cellular health even in the presence of an unfavorable microenvironmental signals.

Importance: The absence of a reliable marker of early-stage knee osteoarthritis (KOA) represents a missed opportunity to develop interventions that restore joint integrity. The use of ultrasonography (US) to measure fat infiltration of muscle, which has been associated with incidence and progression of KOA, is one possible solution. Summarizing the trajectory of fatty infiltration during natural aging and KOA processes and establishing US-implementation as a tool for the early diagnosis of KOA represent essential first steps. Objective: (1) To summarize the alterations in quadriceps muscle quality during healthy aging (young vs. older) and in the setting of KOA (older vs. KOA) using computational approaches, and (2) to validate and translate these findings by applying US assessment of muscle quality in a clinical setting. Design, Setting, Participants: Systematic review with network meta-analysis integrated with a subsequent case-control validation study in an orthopedic clinic. Both analyses evaluated three groups: healthy young, healthy older, and individuals with KOA. Main outcome and Measures: Quadriceps muscle quality assessed by US. Results: Data from a total of 718 healthy aging individuals (young, n = 336; old, n = 382) and 1,046 individuals with KOA (old, n = 625; KOA, n = 421) were synthesized for meta-analyses. As determined by US, older adults displayed poor quadriceps muscle quality compared to young; this decline was significantly exacerbated when individuals had KOA. The network meta-analysis revealed that the presence of KOA significantly accelerated muscle fatty infiltration compared to natural aging. Notably, US findings were comparable to gold-standard imaging modalities of both MRI and CT for fat infiltration in skeletal muscle. The findings from these computational analyses were supported by an US-implemented validation study in a clinical setting, which also identified the vastus medialis as the most sensitive quadricep muscle to predict both the onset and development of KOA. Conclusions and Relevance: This study established accelerated fat deposition in the vastus medialis as a distinct marker for early KOA, as reliably identified by US. These findings expand opportunities for the early diagnosis and treatment for KOA in a clinical setting given the increased cost-efficiency and accessibility of the US system compared to MRI or CT. Trial registration: PROSPERO Identifier: CRD 42022380856