Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by joint pain and physical disability. Aberrant subchondral bone induces pathological changes and is a major source of pain in OA. In the subchondral bone, which is highly innervated, nerves have dual roles in pain sensation and bone homeostasis regulation. The interaction between peripheral nerves and target cells in the subchondral bone, and the interplay between the sensory and sympathetic nervous systems, allow peripheral nerves to regulate subchondral bone homeostasis. Alterations in peripheral innervation and local transmitters are closely related to changes in nociception and subchondral bone homeostasis, and affect the progression of OA. Recent literature has substantially expanded our understanding of the physiological and pathological distribution and function of specific subtypes of neurones in bone. This review summarizes the types and distribution of nerves detected in the tibial subchondral bone, their cellular and molecular interactions with bone cells that regulate subchondral bone homeostasis, and their role in OA pain. A comprehensive understanding and further investigation of the functions of peripheral innervation in the subchondral bone will help to develop novel therapeutic approaches to effectively prevent OA, and alleviate OA pain. Cite this article: Bone Joint Res 2022;11(7):439–452

Knee osteoarthritis (OA) affects an estimated 250 million people worldwide, with a cure yet to be found. Consequently, there is an urgent need to improve our understanding of OA physiopathology. While knee OA has long been mostly described as a loss of cartilage thickness (CTh) and research has focused on this characteristic, the role of bone alterations is rapidly gaining in interest. Analyzing subchondral bone mineral density (sBMD) is particularly interesting because this could inform on the mechanical environment at the knee. However, there is a paucity of data on sBMD in literature mainly because of the lack of prior methods to measure this parameter. A method for 3D sBMD assessment based on computed tomography (CT) scans was recently proposed, thus allowing testing for sBMD differences in knee OA. This study aimed at comparing non-OA and medial OA knees in terms of tibial sBMD and CTh. Specifically, it was hypothesized that sBMD and CTh differ with OA.

Ten knees with severe medial OA and 10 matched non-OA knees were analyzed after ethical approval (50% male; 60 ± 3 years old). The arthro-CT scans of the 20 knees were segmented using custom software to build 3D mesh models of the tibial bone and cartilage. CTh maps were obtained by calculating the distance between cartilage and bone meshes, while sBMD maps were calculated based on the intensity of the CT in the first 3mm of bone. For each knee, the average CTh and sBMD values over the entire medial and lateral compartments were calculated and used to determine the medial-to-lateral (M/L) CTh and sBMD ratios. Unpaired t-tests and receiver operating characteristic (ROC) were used for statistical analysis.

The M/L sBMD ratio was significantly higher in OA compared to non-OA knees (1.14 ± 0.04 vs. 1.08 ± 0.03; p<0.01), whereas the CTh ratio was not significantly different between groups (0.70 ± 0.21 vs. 0.85 ± 0.10; p=0.06). No significant differences were found between OA and non-OA knees for the average medial CTh and sBMD (p>0.4). High classification performance was obtained for the sBMD ratio and low performance for the average sBMD in the medial compartment (areas under the ROC curve of 0.9 and 0.6, respectively). CTh ratio and medial compartment average provided medium classification performances (areas under the curve of 0.7).

This study showed that sBMD differed between non-OA and severe medial OA knees and that sBMD M/L ratio was more sensitive to OA severity than CTh variables. These results brought new insights into the pathogenesis of knee OA, by supporting the idea that sBMD is altered with OA and suggesting that sBMD could play a role in disease development. Indeed, the mechanical stresses on the cartilages are related to the mechanical characteristics of the bones. Indirectly, this study also demonstrated the value of arthro-CT scans to simultaneously assess sBMD and CTh. Additional studies with larger cohorts of patients at different stages of the disease are necessary to better understand when changes in sBMD occur.

Introduction and Objective. Osteoarthritis (OA) is the most common inflammatory and degenerative joint disease. Mesenchymal Stromal Cells (MSCs), with their chondro-protective and immune-regulatory properties, have been considered as a new approach to treat OA. Considering the risk of cell leakage outside the articular space and the poor survival rate after intra-articular (IA) injection, we hypothesized that cell encapsulation in cytoprotective hydrogels could overcome these limitations and provide cells with a suitable 3D microenvironment supporting their biological activity. We previously generated micromolded alginate particles (diameter 150 μm) and demonstrated the long-term viability of microencapsulated MSCs isolated from human adipose tissue (hASCs). Encapsulated cells maintained their in vitro ability to sense and respond to a pro-inflammatory environment (IFN-γ/TNF-α or synovial fluids from OA patients) by secreting PGE. 2. , IDO, HGF and TGF-β. In this study, we evaluated the anti-OA efficacy of these microencapsulated hASCs in a post-traumatic OA model in rabbits. Materials and Methods. OA was surgically induced by anterior cruciate ligament transection (ACLT)-mediated destabilization of the right knee in rabbits (n=24). Eight weeks after surgery, destabilized joints were injected (IA, 26G needle) with 200 μL of either PBS, blank microparticles, non-encapsulated or microencapsulated cells (5×10. 5. cells). Six weeks after injection, rabbits were euthanized and all destabilized (right) and sham-operated (left contralateral) joints were dissected and analyzed for OA severity. Tibial subchondral bone histomorphometric parameters were measured by quantitative micro-computed tomography (micro-CT). Histological sections of samples were analyzed after Safranin-O staining and quantitatively assessed according to a modified Osteoarthritis Research Society International (OARSI) scoring system. Immunohistochemical detection of NITEGE was performed to assess the extracellular matrix degradation. Results. Micro-CT analysis of destabilized joints confirmed that the rabbit ACLT significantly affected the tibial subchondral bone architecture as early as eight weeks, as revealed by significant changes of the subchondral bone parameters of operated joints compared to the sham operated joints. In particular, destabilized joints exhibited a Bone Volume/Tissue Volume ratio (BV/TV) ranging from 53.4% to 56.6%, compared to a mean BV/TV of 65.4% for sham operated joints. All destabilized joints also exhibited a significantly increased modified OARSI score, ranging from 7.4±0.4 for those injected with encapsulated cells to 8.9±0.2 for those injected with PBS, as compared to 4.8±0.4 for sham-operated joints. Of interest, we identified a slight, while not significant, reduction of the severity of OA lesions after injection of microencapsulated cells using the modified OARSI scoring. Finally, semi-quantitative analysis of NITEGE immunostaining revealed a significant increase in all destabilized joints that were injected with PBS or blank microparticles, in comparison with sham ones. On the contrary, NITEGE immunostaining in destabilized joints that were injected with non-encapsulated or encapsulated hASC revealed a significant reduced NITEGE immunostaining, indicating a decreased matrix degradation. Conclusions. Our data suggest that the microencapsulated hASCs exerted their anti-OA properties after IA injection in rabbit knees, as evidenced by the tendency toward a reduced modified OARSI score, and most importantly a significant reduction in NITEGE immunostaining associated matrix degradation. Further studies are now warranted to investigate the anti-OA efficacy of microencapsulated hASCs in the long-term

Osteoarthritis (OA) is a chronic degenerative joint disease with cartilage degeneration, subchondral bone sclerosis, synovial inflammation and osteophyte formation. Sensory nerves play an important role in bone metabolism and in the progression of inflammation. This study explored the effects of capsaicin-induced sensory nerve denervation on OA progression in mice. This study was approved by the Institutional Animal Care and Use Committee. OA was induced via destabilization of the medial meniscus (DMM). Sensory denervation was induced by subcutaneous injection of capsaicin (90mg/kg) one week prior to DMM. One week after capsaicin injection, sensory denervation in the tibia was confirmed by immunofluorescent staining with calcitonin gene-related peptide (CGRP)-specific antibodies. Four weeks after DMM, micro-CT scans, histological analysis and RT-PCR tests were performed to evaluate OA progression. Statistical analysis was performed using SPSS 13. P values of less than 0.05 were considered statistically significant. Subcutaneous injection of capsaicin successfully induced tibial sensory denervation (n=3), which aggravated OA by increasing subchondral bone resorption. The Osteoarthritis Research Society International (OARSI) score of the capsaicin+DMM group (n=8) (11.81±2.92) was significantly higher (P=0.003) than the score of the vehicle+DMM group (n=8) (8.31±1.80). The BV/TV of the tibial subchondral bone in the capsaicin+DMM group (n=8) was 55.67%±3.08, which was significantly lower (P < 0 .001) than in the vehicle+DMM group (n=8) (86.22%±1.92). In addition, the level of expression of somatostatin in the capsaicin+DMM group (n=8) was lower than in the vehicle+DMM group (n=8) (P=0.007). Capsaicin-induced sensory denervation increased tibial subchondral bone resorption, reduced the expression of somatostatin and eventually exacerbated the existing cartilage degeneration in mice. Despite capsaicin is often used clinically to relieve OA pain, its safety is still controversial according to the OARSI guidelines for the non-surgical management of knee osteoarthritis. The findings of our study suggest that application of capsaicin, although effective in relieving pain, may accelerate the progression of existing OA

The arcOGEN study identified the 9q33.1 locus as associated with hip osteoarthritis (OA) in females. TRIM32 lies within this locus and may have biological relevance to OA; it encodes a protein with E3 ubiquitin ligase activity. Sanger sequencing of TRIM32 in the youngest 500 female patients with hip OA from the arcOGEN study identified genetic polymorphisms in the proximal promoter, and 3'untranslated region of TRIM32 that are disproportionately represented in female patients with hip OA compared to the control population. Reduced expression of TRIM32 was identified in femoral head articular chondrocytes from patients with hip OA compared to control patients. Trim32 knockout resulted in increased aggrecanolysis in murine femoral head explants. Murine chondrocytes deficient in Trim32 exhibited increased expression of mature chondrocyte markers following anabolic cytokine stimulation, and increased expression of hypertrophic chondrocyte markers following catabolic cytokine stimulation. Trim32 knockout mice demonstrated increased cartilage degradation and tibial subchondral bone changes after surgically-induced knee joint instability. Increased cartilage degradation and medial knee subchondral bone changes were also identified in aged Trim32 knockout mice. These results further implicate TRIM32 in the genetic predisposition to OA, and indicate a role for TRIM32 in the joint degeneration evident in OA. These results support the further study of TRIM32 in the pathophysiology of OA and development of novel therapeutic strategies to manage OA

Aims

cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect.

Aims

Post-traumatic osteoarthritis (PTOA) is a subset of osteoarthritis (OA). The gut microbiome is shown to be involved in OA. However, the effect of exercise on gut microbiome in PTOA remains elusive.

Aims

Osteoarthritis (OA) is the most prevalent systemic musculoskeletal disorder, characterized by articular cartilage degeneration and subchondral bone (SCB) sclerosis. Here, we sought to examine the contribution of accelerated growth to OA development using a murine model of excessive longitudinal growth. Suppressor of cytokine signalling 2 (SOCS2) is a negative regulator of growth hormone (GH) signalling, thus mice deficient in SOCS2 (Socs2^-/-) display accelerated bone growth.

Aims

Osteoarthritis (OA) is a disabling joint disorder and mechanical loading is an important pathogenesis. This study aims to investigate the benefits of less mechanical loading created by intermittent tail suspension for knee OA.