Chondroprotective Effects of a Single PRP Injection in a Spontaneous Osteoarthritis Model of Dunkin Hartley Guinea Pig: An Immunohistochemical Analysis.

Purpose of the Study: The evaluation of anti-apoptotic and chondroprotective properties of a single injection of PRP using immunohistochemistry (IHC). Methods: This was a placebo-controlled blinded experimental study. Ten healthy Dunkin Hartley guinea pigs were selected. One knee of each animal was injected with a single injection of PRP (Group A); the contralateral knee acted as a control and was injected with a single injection of normal saline (Group B). These groups were further divided into A3 and B3 based on the timeline of animal sacrifice (3 months) and A6 and B6 (6 months). The formalin-preserved articular cartilage blocks were subjected to IHC to stain Aggrecan, Caspase-3, and Collagen-2. Results: The mean IHC score was significantly low for Caspase-3 (p-0.029) in intervention group (A3) in comparison to placebo control group (B3) pointing towards decreased apoptosis. The mean IHC values were significantly higher for Collagen II (p-0.011) for intervention group (A6) in contrast to control group (B6); values were also significantly low for Caspase-3 (p-0.029) in A6 as compared to B6. The mean Caspase-3 values were significantly higher in A6 as compared to A3 (p-0.029). Conclusion: The impact of a solitary injection of PRP on upregulation of anabolic pathways inside cartilage is relatively slower as compared to its effect on downregulation of apoptotic pathways. Even a single PRP injection holds the potential to change cartilage microenvironment, but the effects are not long lasting.

Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis.

Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21- and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs from in vitro cultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.

Naturally Occurring Osteoarthritis Features and Treatments: Systematic Review on the Aged Guinea Pig Model.

To date, several in vivo models have been used to reproduce the onset and monitor the progression of osteoarthritis (OA), and guinea pigs represent a standard model for studying naturally occurring, age-related OA. This systematic review aims to characterize the guinea pig for its employment in in vivo, naturally occurring OA studies and for the evaluation of specific disease-modifying agents. The search was performed in PubMed, Scopus, and Web of Knowledge in the last 10 years. Of the 233 records screened, 49 studies were included. Results showed that within a relatively short period of time, this model develops specific OA aspects, including cartilage degeneration, marginal osteophytes formation, and subchondral bone alterations. Disease severity increases with age, beginning at 3 months with mild OA and reaching moderate-severe OA at 18 months. Among the different strains, Dunkin Hartley develops OA at a relatively early age. Thus, disease-modifying agents have mainly been evaluated for this strain. As summarized herein, spontaneous development of OA in guinea pigs represents an excellent model for studying disease pathogenesis and for evaluating therapeutic interventions. In an ongoing effort at standardization, a detailed characterization of specific OA models is necessary, even considering the main purpose of these models, i.e., translatability to human OA.

Mice Lacking Wnt9a or Wnt4 Are Prone to Develop Spontaneous Osteoarthritis With Age and Display Alteration in Either the Trabecular or Cortical Bone Compartment.

Osteoarthritis (OA) is a common degenerative disease of the joint, with a complex multifactorial not yet fully understood etiology. Over the past years, the Wnt signaling pathway has been implicated in osteoarthritis. In a recent genomewide association study (GWAS), the chromosomal location on chromosome 1, linked to the Wnt3a-Wnt9a gene locus, was identified as the most significant locus associated with a thumb osteoarthritis endophenotype. Previously, it was shown that WNT9a is involved in maintaining synovial cell identity in the elbow joint during embryogenesis. Here, we report that the conditional loss of Wnt9a in the Prx1-Cre expressing limb mesenchyme or Prg4-CreER expressing cells predispositions the mice to develop spontaneous OA-like changes with age. In addition, the trabecular bone volume is altered in these mice. Similarly, mice with a conditional loss of Wnt4 in the limb mesenchyme are also more prone to develop spontaneously OA-like joint alterations with age. These mice display additional alterations in their cortical bone. The combined loss of Wnt9a and Wnt4 increased the likelihood of the mice developing osteoarthritis-like changes and enhanced disease severity in the affected mice. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Alteration of the gut microbiota in rhesus monkey with spontaneous osteoarthritis.

BACKGROUND: The spontaneous osteoarthritis (OA) in rhesus macaque is similar to OA in human, which maintains an upright body posture and shows very similar biomechanical properties of bones to humans. At present, there is no good treatment for OA. This study aims to explore relationship between OA and intestinal microbiota, and provide a reference for the treatment of clinical OA. RESULTS: We collected colonic contents of the 20 rhesus macaque (6-15 years old, female) for intestinal microbiota analysis by metagenomics sequencing, of which 10 were spontaneous OA monkeys and 10 were normal monkeys. Our results showed the diversity of gut microbiota in monkeys with OA was decreased compared to the normal monkeys (p = 0.16). Mollicutes, Tenericutes, Coprobacillus and Faecalitalea may be biomarkers for the monkeys of OA. Lactobacillus found significantly increased in OA monkeys. Prevotella and Ruminococcus were higher in the normal group than OA group. Zinc/manganese transport system permease protein (p = 0.0011) and Cyclopropane-fatty-acyl-phospholipid synthase (p = 0.0012) are a microbiota metabolic pathway related to cartilage production. CONCLUSIONS: Our results indicate that the diversity and composition of intestinal microbiota in monkeys with OA are different compared to the normal monkeys. we have found microbes that may be a biomarker for the diagnosis of osteoarthritis. Functional analysis of the microbiota also predicts cartilage damage in the monkeys with osteoarthritis. Non-human primates are closely related to humans, so this study can provide a reference for the development of drugs for the treatment of OA.

Trend of Cadherin-11 expression and its impact on cartilage degradation in the temporomandibular joints of guinea pigs with spontaneous osteoarthritis.

BACKGROUND: This study aims to investigate spatial and temporal changes in cadherin-11 (CAD-11) expression and their effects on cartilage degeneration in the temporomandibular joint (TMJ) of guinea pigs with spontaneous osteoarthritis (OA). METHODS: Dunkin-Hartley (DH) and Bristol strain 2 (BS2) guinea pigs at ages of 1, 3, 6, 9, and 12 months were categorized into two groups and analyzed. The bilateral TMJ condyles of DH and BS2 guinea pigs were harvested and fixed. The distribution and expression profiles of CAD-11, collagen type II, and matrix metalloproteinase 3 (MMP-3) were detected by immunohistological assays. Histological micrographs of the condyle cartilage were obtained and analyzed. RESULTS: Osteoarthritis can be spontaneously induced by mechanical stress in DH guinea pigs. The main histopathological changes in the TMJ structure and increased expression of MMP-3 occurred within 6-9 months of ages in DH guinea pigs with spontaneous OA. By contrast, minimal to mild cartilage degradations were observed in the TMJ of BS2 guinea pigs even at the age of 12 months. From as early as 3 months of age, the expression levels of CAD-11 were upregulated in the TMJ of DH guinea pigs compared with those in BS2 animals. CAD-11 expression differed between the two groups at 12 months of age. CONCLUSIONS: Increased CAD-11 expression within cartilage is associated with the development and progression of OA between the two strains of guinea pigs. Therefore, CAD-11 expression in TMJ could be an important predisposing factor for the development of spontaneous OA.

Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-ß signaling.

Transforming growth factor-ß (TGF-ß) has been demonstrated as a potential therapeutic target in osteoarthritis. However, beneficial effects of TGF-ß supplement and inhibition have both been reported, suggesting characterization of the spatiotemporal distribution of TGF-ß during the whole time course of osteoarthritis is important. To investigate the activity of TGF-ß in osteoarthritis progression, we collected knee joints from Dunkin-Hartley (DH) guinea pigs at 3, 6, 9, and 12-month old (n = 8), which develop spontaneous osteoarthritis in a manner extraordinarily similar to humans. Via histology and micro-computed tomography (CT) analysis, we found that the joints exhibited gradual cartilage degeneration, subchondral plate sclerosis, and elevated bone remodeling during aging. The degenerating cartilage showed a progressive switch of the expression of phosphorylated Smad2/3 to Smad1/5/8, suggesting dual roles of TGF-ß/Smad signaling during chondrocyte terminal differentiation in osteoarthritis progression. In subchondral bone, we found that the locations and age-related changes of osterix(+) osteoprogenitors were in parallel with active TGF-ß, which implied the excessive osteogenesis may link to the activity of TGF-ß. Our study, therefore, suggests an association of cartilage degeneration and excessive bone remodeling with altered TGF-ß signaling in osteoarthritis progression of DH guinea pigs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:763-770, 2016.