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Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_7 | Pages 55 - 55
4 Apr 2023
Ge Q Shi Z Ying J Chen J Yuan W Wang P Chen D Feng X Tong P Jin H
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TGF-β/Smad2 signaling is considered to be one of the important pathways involved in osteoarthritis (OA) and protein phosphatase magnesium-dependent 1A (PPM1A) functions as an exclusive phosphatase of Smad2 and regulates TGF-β signaling, here, we investigated the functional role of PPM1A in OA pathogenesis.

PPM1A expressions in both human OA cartilage and experimental OA mice chondrocytes were analyzed immunohistochemically. Besides, the mRNA and protein expression of PPM1A induced by IL-1β treatment were also detected by q-PCR and immunofluorescence in vitro. OA was induced in PPM1A knockout (KO) mice by destabilization of the medial meniscus (DMM), and histopathological examination was performed. OA was also induced in wild-type (WT) mice, which were then treated with an intra-articular injection of a selective PPM1A inhibitor for 8 weeks.

PPM1A protein expressions were increased in both human OA cartilage and experimental OA mice chondrocytes. We also found that treatment with IL-1β in mouse primary chondrocytes significantly increased both mRNA and protein expression of PPM1A in vitro. Importantly, our data showed that PPM1A deletion could substantially protect against surgically induced OA. Concretely, the average OARSI score and quantification of BV/TV of subchondral bone in KO mice were significantly lower than that in WT mice 8 weeks after DMM surgery. Besides, TUNEL staining revealed a significant decrease in apoptotic chondrocytes in PPM1A-KO mice with DMM operation. With OA induction, the rates of chondrocytes positive for Mmp-13 and Adamts-5 in KO mice were also significantly lower than those in WT mice. Moreover, compared with WT mice, the phosphorylation of Smad2 in chondrocytes was increased in KO mice underwent DMM surgery. However, articular-injection with SD-208, a selective inhibitor of TGF-β/Smad2 signaling could significantly abolish the chondroprotective phenotypes in PPM1A-KO mice. Additionally, both cartilage degeneration and subchondral bone subchondral bone sclerosis in DMM model were blunted following intra-articular injection with BC-21, a small-molecule inhibitor for PPM1A.

Our study demonstrated that PPM1A inhibition attenuates OA by regulating TGF-β/Smad2 signaling. Furthermore, PPM1A is a potential target for OA treatment and BC-21 may be employed as alternative therapeutic agents for the management of OA.


Orthopaedic Proceedings
Vol. 100-B, Issue SUPP_3 | Pages 44 - 44
1 Apr 2018
Warnecke D Balko J Schild NB Wang P Bieger R Ignatius A Mizaikoff B Reichel H Dürselen L
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Introduction

With processing age, meniscus degeneration occurs which is often associated with osteoarthritis. Existing data about the influence of degeneration on the biomechanical properties of the meniscus are still contradictory, or completely unknown regarding the hydraulic permeability. Thus, the aim of this study was to characterise the biomechanical properties and structural composition of the meniscal tissue depending on its degree of degeneration.

Methods

Menisci of 24 TKR-patients (≈67.1 yrs.) were harvested and the degeneration of each region (pars anterior PA, pars intermedia PI, pars posterior PP) classified according to Pauli et al. For biomechanical characterisation, confined compression tests (20% strain; velocity: 3%h0/min, relaxation time: 1h) to determine equilibrium modulus (HA) and hydraulic permeability (k) and tensile tests (velocity: 5%l0/min) to determine the tensile modulus were performed. Therefore, cylindrical (Ø= 4.6mm, initial height h0≈ 2.3mm) and dumbbell-shaped (3.5mm × 1.4mm × 3.5mm) samples were punched out of each region and flattened to achieve parallel surfaces. Additionally, collagen and proteoglycan (PG) content were analysed by calculating the area-under-curve of their specific wavelength ranges (1293–1356cm−1 and 980–1120cm−1, respectively) using infrared (IR) spectroscopy. To identify differences regarding the meniscus regions or its degeneration, a statistically mixed model was used.


Bone & Joint Research
Vol. 6, Issue 4 | Pages 253 - 258
1 Apr 2017
Hsu C Lin C Jou I Wang P Lee J

Objectives

Osteoarthritis (OA) is the most common form of arthritis, affecting approximately 15% of the human population. Recently, increased concentration of nitric oxide in serum and synovial fluid in patients with OA has been observed. However, the exact role of nitric oxide in the initiation of OA has not been elucidated. The aim of the present study was to investigate the role of nitric oxide in innate immune regulation during OA initiation in rats.

Methods

Rat OA was induced by performing meniscectomy surgery while cartilage samples were collected 0, 7, and 14 days after surgery. Cartilage cytokine levels were determined by using enzyme-linked immunosorbent assay, while other proteins were assessed by using Western blot