Aims

This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms.

Aims. Rotator cuff (RC) injuries are characterized by tendon rupture, muscle atrophy, retraction, and fatty infiltration, which increase injury severity and jeopardize adequate tendon repair. Epigenetic drugs, such as histone deacetylase inhibitors (HDACis), possess the capacity to redefine the molecular signature of cells, and they may have the potential to inhibit the transformation of the fibro-adipogenic progenitors (FAPs) within the skeletal muscle into adipocyte-like cells, concurrently enhancing the myogenic potential of the satellite cells. Methods. HDACis were added to FAPs and satellite cell cultures isolated from mice. The HDACi vorinostat was additionally administered into a RC injury animal model. Histological analysis was carried out on the isolated supra- and infraspinatus muscles to assess vorinostat anti-muscle degeneration potential. Results. Vorinostat, a HDACi compound, blocked the adipogenic transformation of muscle-associated FAPs in culture, promoting myogenic progression of the satellite cells. Furthermore, it protected muscle from degeneration after acute RC in mice in the earlier muscle degenerative stage after tenotomy. Conclusion. The HDACi vorinostat may be a candidate to prevent early muscular degeneration after RC injury. Cite this article: Bone Joint Res 2024;13(4):169–183

Aims

Pigment epithelium-derived factor (PEDF) is known to induce several types of tissue regeneration by activating tissue-specific stem cells. Here, we investigated the therapeutic potential of PEDF 29-mer peptide in the damaged articular cartilage (AC) in rat osteoarthritis (OA).

Aims

Rotator cuff muscle atrophy and fatty infiltration affect the clinical outcomes of rotator cuff tear patients. However, there is no effective treatment for fatty infiltration at this time. High-intensity interval training (HIIT) helps to activate beige adipose tissue. The goal of this study was to test the role of HIIT in improving muscle quality in a rotator cuff tear model via the β3 adrenergic receptor (β3AR).

Aims. The decrease in the number of satellite cells (SCs), contributing to myofibre formation and reconstitution, and their proliferative capacity, leads to muscle loss, a condition known as sarcopenia. Resistance training can prevent muscle loss; however, the underlying mechanisms of resistance training effects on SCs are not well understood. We therefore conducted a comprehensive transcriptome analysis of SCs in a mouse model. Methods. We compared the differentially expressed genes of SCs in young mice (eight weeks old), middle-aged (48-week-old) mice with resistance training intervention (MID+ T), and mice without exercise (MID) using next-generation sequencing and bioinformatics. Results. After the bioinformatic analysis, the PI3K-Akt signalling pathway and the regulation of actin cytoskeleton in particular were highlighted among the top ten pathways with the most differentially expressed genes involved in the young/MID and MID+ T/MID groups. The expression of Gng5, Atf2, and Rtor in the PI3K-Akt signalling pathway was higher in the young and MID+ T groups compared with the MID group. Similarly, Limk1, Arhgef12, and Araf in the regulation of the actin cytoskeleton pathway had a similar bias. Moreover, the protein expression profiles of Atf2, Rptor, and Ccnd3 in each group were paralleled with the results of NGS. Conclusion. Our results revealed that age-induced muscle loss might result from age-influenced genes that contribute to muscle development in SCs. After resistance training, age-impaired genes were reactivated, and age-induced genes were depressed. The change fold in these genes in the young/MID mice resembled those in the MID + T/MID group, suggesting that resistance training can rejuvenate the self-renewing ability of SCs by recovering age-influenced genes to prevent sarcopenia. Cite this article: Bone Joint Res 2022;11(2):121–133

Myxofibrosarcoma (MFS) is the second most common subtype of soft tissue sarcoma (STS) and is associated with a high rate of local recurrence after resection. These tumours frequently present with peri-lesional edema, termed “tumour tails” on staging MRI scans [1]. Tumour tails(TT) may contain satellite neoplastic cells or can represent benign reactive edema. There are no clear radiological features to distinguish malignant from reactive peri-lesional edema which limits accurate surgical planning, resulting in either high rates of inadvertently positive resection margins and local recurrences or overly-aggressive resections which negatively impact function and increase morbidity [2]. The objective of this pilot study was to prospectively study a cohort of MFS patients with TTs in an attempt to identify radiological features that predict which type of edema is malignant and requires resection together with the main tumour mass. Patients diagnosed with MFS on biopsy at an orthopaedic oncology referral centre between January 1-December 31 2018 who also had TTs on staging MRI scans were prospectively recruited for the study. Tumours were treated with wide surgical excision, including the TTs, and (neo)adjuvant radiotherapy as per institutional protocol. Staging MRI scans were reviewed in a blinded fashion by two musculoskeletal radiologists to distinguish malignant from reactive TTs. The main tumour mass underwent standard histological evaluation while the regions encompassing the TTs were photographed and sectioned into grids. Each tissue section was examined histologically for the presence of satellite neoplastic cells based on morphological criteria. Radiological and histological findings were compared. Six patients met the inclusion criteria and underwent analysis. All tumours were located in the extremities and were deep to fascia. Mean age at presentation was 67 years (range 51 – 85), with a male:female ratio of 4:2. All patients received radiotherapy (50 Gy), either pre- (n=4) or post-operatively (n=2) based on multidisciplinary tumor board discussion or enrolment in a prospective clinical trial. Radiologically, TTs were labelled as malignant in four patients (66.7%) and as benign TTs in two others. The tails were recognised to be malignant due to the differing signal characteristics to reactive edema on mixed MRI sequences. The radiological evaluation correlated exactly with histological analysis, as satellite neoplastic cells were identified microscopically in the same four cases in which the TTs were designated to be malignant by MRI (specificity&sensitivity=100%). Surgical resection margins were microscopically positive in 50% of cases in the TTs themselves, and 75% of cases in which TTs were designated as malignant on staging MRI. “The malignant nature of peri-lesional edema in MFS, also known as the TT, was accurately predicted in this small pilot study based on specific radiological features which correlated exactly with histologic identification of isolated tumor cells. These findings validate development of a larger prospective study to recruit additional patients with tumor tails beyond just MFS, in order to more robustly study the correlation between the MRI appearance and histological distribution of satellite sarcoma cells in peri-lesional edema in STS. We are already recruiting to this expanded radiological-histological investigation including evaluation of additional novel MRI sequences

MicroRNAs (miRNAs) are a class of small non-coding RNAs that have emerged as potential predictive, prognostic, and therapeutic biomarkers, relevant to many pathophysiological conditions including limb immobilization, osteoarthritis, sarcopenia, and cachexia. Impaired musculoskeletal homeostasis leads to distinct muscle atrophies. Understanding miRNA involvement in the molecular mechanisms underpinning conditions such as muscle wasting may be critical to developing new strategies to improve patient management. MicroRNAs are powerful post-transcriptional regulators of gene expression in muscle and, importantly, are also detectable in the circulation. MicroRNAs are established modulators of muscle satellite stem cell activation, proliferation, and differentiation, however, there have been limited human studies that investigate miRNAs in muscle wasting. This narrative review summarizes the current knowledge as to the role of miRNAs in the skeletal muscle differentiation and atrophy, synthesizing the findings of published data. Cite this article: Bone Joint Res 2020;9(11):798–807

Objectives

Activation of the leptin pathway is closely correlated with human knee cartilage degeneration. However, the role of the long form of the leptin receptor (Ob-Rb) in cartilage degeneration needs further study. The aim of this study was to determine the effect of increasing the expression of Ob-Rb on chondrocytes using a lentiviral vector containing Ob-Rb.

Aims

Improvements in the evaluation of outcomes following peripheral nerve injury are needed. Recent studies have identified muscle fatigue as an inevitable consequence of muscle reinnervation. This study aimed to quantify and characterize muscle fatigue within a standardized surgical model of muscle reinnervation.

Physical outcome following total knee arthroplasty is variable. Satellite cells are undifferentiated myogenic precursors considered to be muscle stem cells. We hypothesised that; the recovery of muscle strength and physical function following knee arthroplasty would be influenced by the underlying number of muscle satellite cells. 16 patients provided a distal quadriceps muscle biopsy at time of surgery. Satellite cells were identified with a primary mouse antibody for Pax7 – a cytoplasmic protein marker, and the myonuclei with DAPI. Positive cells were identified on the basis of immunofluorescent staining in association with nuclear material, and confirmed by position under the basal lamina. Patient function was assessed using a validated physical assessment protocol, the Aggregated Locomotor Function (ALF) score, muscle strength assessed using the leg extensor power-rig, and clinical outcome assessed with the Oxford Knee Score (OKS) pre-operatively and at 1 year post operatively. Muscle satellite cell content varied amongst the patient group (Positive Staining Index 3.1 to 11.4). Satellite cell content at time of surgery correlated with change in outcomes between pre-operative and 1 year assessments in all assessed parameters (ALF, r = 0.31; muscle power, r = 49; OKS, r = 0.33). Regression analysis employing a forward stepwise selection technique employed satellite cell volume in models of pre-operative to 1 year change for all outcome parameters. Physical function (satellite cell content, patient age and pre-operative ALF score) adjusted R2 = 0.92; Muscle power (pre-operative power and satellite cell content) adjusted R2 = 0.38; Clinical outcome (pre-operative OKS and satellite cell content) adjusted R2 = 0.28. Muscle satellite cell content influences recovery of muscle power and physical function following total knee arthroplasty. Importantly it is also associated with change in clinical scores; suggesting it to be a biomarker for patient outcomes

Objectives

Rotator cuff tears are among the most common and debilitating upper extremity injuries. Chronic cuff tears result in atrophy and an infiltration of fat into the muscle, a condition commonly referred to as ‘fatty degeneration’. While stem cell therapies hold promise for the treatment of cuff tears, a suitable immunodeficient animal model that could be used to study human or other xenograft-based therapies for the treatment of rotator cuff injuries had not previously been identified.

Objectives

Traumatic brachial plexus injury causes severe functional impairment of the arm. Elbow flexion is often affected. Nerve surgery or tendon transfers provide the only means to obtain improved elbow flexion. Unfortunately, the functionality of the arm often remains insufficient. Stem cell therapy could potentially improve muscle strength and avoid muscle-tendon transfer. This pilot study assesses the safety and regenerative potential of autologous bone marrow-derived mononuclear cell injection in partially denervated biceps.

Objectives. Lower limb muscle power is thought to influence outcome following total knee replacement (TKR). Post-operative deficits in muscle strength are commonly reported, although not explained. We hypothesised that post-operative recovery of lower limb muscle power would be influenced by the number of satellite cells in the quadriceps muscle at time of surgery. . Methods. Biopsies were obtained from 29 patients undergoing TKR. Power output was assessed pre-operatively and at six and 26 weeks post-operatively with a Leg Extensor Power Rig and data were scaled for body weight. Satellite cell content was assessed in two separate analyses, the first cohort (n = 18) using immunohistochemistry and the second (n = 11) by a new quantitative polymerase chain reaction (q-PCR) protocol for Pax-7 (generic satellite cell marker) and Neural Cell Adhesion Molecule (NCAM; marker of activated cells). Results. A significant improvement in power output was observed post-operatively with a mean improvement of 19.7 W (95% confidence interval (CI) 14.43 to 30.07; p < 0.001) in the first cohort and 27.5 W (95% CI 13.2 to 41.9; p = 0.002) in the second. A strong correlation was noted between satellite cell number (immunohistochemistry) and improvement in patient power output (r = 0.64, p = 0.008). Strong correlation was also observed between the expression of Pax-7 and power output (r = 0.79, p = 0.004), and the expression of NCAM and power output (r = 0.84, p = 0.001). The generic marker explained 58% of the variation in power output, and the marker of activated cells 67%. Conclusions. Muscle satellite cell content may determine improvement in lower limb power generation (and thus function) following TKR

Introduction. Recovery of muscle strength following Total Knee Replacement (TKR) is variable, and can affect the resultant function of the patient. Satellite cells are undifferentiated myogenic precursors considered to be muscle stem cells that lie quiescently around the muscle fibre. These cells repair damaged fibres and have the potential to generate new muscle fibres. Therefore, theoretically, they could be associated with the variation in muscle recovery following surgery. We hypothesised that the recovery of muscle strength following knee replacement in a given patient would be influenced by the underlying number of satellite cells in that patient. Methods. 20 patients undergoing TKR were recruited from the waiting list of a single consultant. A muscle biopsy was taken at the time of surgery from the distal quadriceps. This was fixed in paraffin wax, and sections obtained. Satellite cells were identified with a primary mouse antibody for Pax7 - a cytoplasmic protein marker - and an immunofluorescent goat anti-mouse secondary. Slides were counterstained with DAPI to stain the myonuclei. The positive staining index (PSI) was calculated (number of satellite cells/total number of myonuclei x 100). Recovery of muscle (quadriceps) strength was assessed using the leg extensor power-rig (LegRig) pre-operatively, at 6 and 26 weeks post-operatively. Statistical analysis was performed using the Minitab version 15 software, the level of significance was set as p = 0.05. Results. 3 patients were unable to provide follow-up data. The number of satellite cells amongst individual patients in our cohort varied (PSI 3.07 to 11.35). Improvement in muscle power post-op also varied (0 to 70 W) between the 6 and 26 weeks assessment periods. This improvement in wattage generated between assessments reflected a relative improvement of between 0 and 60% in the strength to bodyweight ratio of these patients. The improvement in muscle power correlated with the satellite cell numbers (determined at the time of surgery). This was true for both absolute improvement in wattage generated (r = 0.54 p= 0.038) and also the improvement in strength to body weight ratio (r = 0.47 p = 0.06). Linear regression analysis demonstrated that the relative satellite cell number accounted for 30% of the improvement in muscle power. Discussion. We have for the first time demonstrated that the magnitude of improvement in muscle strength following TKR may be influenced by the patient's underlying pool of muscle satellite cells, with up to 30% of the variation of improvement in our cohort attributable to the satellite cell population

Bone morphogenetic proteins (BMPs) are able to induce osteogenic differentiation in many cells, including muscle cells. However, the actual contribution of muscle cells to bone formation and repair is unclear. Our objective was to examine the capacity of myogenic cells to contribute to BMP-induced ectopic bone formation and fracture repair. Osteogenic gene expression was measured by quantitative PCR in osteoprogenitors, myoblasts, and fibroblasts following BMP-2 treatment. The MyoD-Cre x ROSA26R and MyoD-Cre x Z/AP mouse strains were used to track the fate of MyoD+ cells in vivo. In these double-transgenic mice, MyoD+ progenitors undergo a permanent recombination event to induce reporter gene expression. Ectopic bone was produced by the intramuscular implantation of BMP-7. Closed tibial fractures and open tibial fractures with periosteal stripping were also performed. Cellular contribution was tracked at one, two and three week time points by histological staining. Osteoprogenitors and myoblasts exhibited comparable expression of early and late bone markers; in contrast bone marker expression was considerably less in fibroblasts. The sensitivity of cells to BMP-2 correlated with the expression of BMP receptor-1a (Bmpr1a). Pilot experiments using the MyoD-Cre x Rosa26R mice identified a contribution by MyoD expressing cells in BMP-induced ectopic bone formation. However, false positive LacZ staining in osteoclasts led us to seek alternative systems such as the MyoD-cre x Z/AP mice that have negligible background staining. Initially, a minor contribution from MyoD expressing cells was noted in the ectopic bones in the MyoD-cre x Z/AP mice, but without false positive osteoclast staining. Soft tissue trauma usually precedes the formation of ectopic bone. Hence, to mimic the clinical condition more precisely, physical injury to the muscle was performed. Traumatising the muscle two days prior to BMP-7 implantation: (1) induced MyoD expression in quiescent satellite cells; (2) increased ectopic bone formation; and (3) greatly enhanced the number of MyoD positive cells in the ectopic bone. In open tibial fractures the majority of the initial callus was MyoD+ indicating a significant contribution by myogenic cells. In contrast, closed fractures with the periosteum intact had a negligible myogenic contribution. Myoblasts but not fibroblasts were highly responsive to BMP stimulation and this was associated with BMP receptor expression. Our transgenic mouse models demonstrate for the first time that muscle progenitors can significantly contribute to ectopic bone formation and fracture repair. This may have translational applications for clinical orthopaedic therapies

Background: Traumatic brachial plexus (BP) injuries may cause loss of elbow flexion. After nerve surgery active elbow flexion often remains insufficient. Muscle strength improvement via cell therapy would be a potential option and could avoid muscle transfer surgery. The primary objective of this pilot study was to assess the safety and feasibility of autologous bone marrow (BM)-derived mononuclear cell (MNC) injection in partly denervated m. biceps brachii of BP patients. Secondary, this study has focused on the myogenic potential of BM-derived MNC by assessing the morphological and functional improvement of the biceps. Methods: Nine adult BP patients with insufficient force recovery of elbow flexion were included. Three escalating doses (0.9, 4 and 8 * 108) of MNCs were injected in the m. biceps brachii (group A, B and C). In group A, BM was aspirated under local anesthesia (60 ml). In group B and C, BM was aspirated in combination with a muscle tendon transfer (Steindler flexorplasty) under general anesthesia (350 and 650 ml respectively). A muscle biopsy was performed before and 3 months after transplantation. Furthermore, quantitative needle EMG, CT-scan and clinical function was obtained at pre-transplantation and at 3 and 6 months follow-up. The EMG and CT-scan data were blinded during analysis. Results: No negative side effects were observed. Biopsies showed an increase of 80% in myofiber diameter (P = 0.007), 51% in satellite cells (P = 0.045), 83% in capillary to myofiber ratio (P < 0.001) and a decrease of 51% in fibrosis (P = 0.012). Histological changes were most apparent in group B with an increase of 126% in myofiber diameter (P = 0.019), 100% in capillary to myofiber ratio (P = 0.027), and a decrease of 70% in fibrosis (P = 0.023). EMG demonstrated an increase of 36% in amplitude (P = 0.045), 29% in duration (P = 0.005) and 29% in number of phases of the motor unit potentials (P = 0.002). CT-scan analysis showed a decrease of 48% in mean muscle density (P = 0.009). Discussion: This study shows that BM-derived MNC transplantation in a partly denervated muscle of traumatic PB patients is safe and feasible. Muscle improvement was observed in muscle biopsies. Furthermore, changes in EMGs and CT-scans were also suggestive for muscle regeneration. The BM dose applied in group B could represent the optimal dose to enhance partly denervated muscles. The results of the present study require confirmation in a placebo-controlled study

The nervous system is known to be involved in inflammation and repair. We aimed to determine the effect of physical activity on the healing of a muscle injury and to examine the pattern of innervation. Using a drop-ball technique, a contusion was produced in the gastrocnemius in 20 rats. In ten the limb was immobilised in a plaster cast and the remaining ten had mobilisation on a running wheel. The muscle and the corresponding dorsal-root ganglia were studied by histological and immunohistochemical methods.

In the mobilisation group, there was a significant reduction in lymphocytes (p = 0.016), macrophages (p = 0.008) and myotubules (p = 0.008) between three and 21 days. The formation of myotubules and the density of nerve fibres was significantly higher (both p = 0.016) compared with those in the immobilisation group at three days, while the density of CGRP-positive fibres was significantly lower (p = 0.016) after 21 days.

Mobilisation after contusional injury to the muscle resulted in early and increased formation of myotubules, early nerve regeneration and progressive reduction in inflammation, suggesting that it promoted a better healing response.

The anatomical studies, basic to our understanding of lumbar spine innervation through the sinu-vertebral nerves, are reviewed. Research in the 1980s suggested that pain sensation was conducted in part via the sympathetic system. These sensory pathways have now been clarified using sophisticated experimental and histochemical techniques confirming a dual pattern. One route enters the adjacent dorsal root segmentally, whereas the other supply is non-segmental ascending through the paravertebral sympathetic chain with re-entry through the thoracolumbar white rami communicantes.

Sensory nerve endings in the degenerative lumbar disc penetrate deep into the disrupted nucleus pulposus, insensitive in the normal lumbar spine. Complex as well as free nerve endings would appear to contribute to pain transmission.

The nature and mechanism of discogenic pain is still speculative but there is growing evidence to support a ‘visceral pain’ hypothesis, unique in the muscloskeletal system. This mechanism is open to ‘peripheral sensitisation’ and possibly ‘central sensitisation’ as a potential cause of chronic back pain.