Increasing the Medium Osmolarity Reduces the Inflammatory Status of Human OA Chondrocytes and Increases Their Responsiveness to GDF-5

Abstract

The environment surrounding chondrocytes changes drastically in osteoarthritis (OA). For instance, the osmolarity in cartilage (ranging from 350 to 460 mOsm in healthy tissue) decreases during the progression of OA, reaching 270 mOsm. The objective of this study was to evaluate how osmolarity influences human OA chondrocytes. For this purpose, the osmolarity of the culture medium (340 mOsm) was increased to 380, 420 or 460 mOsm and its effect on the phenotype, matrix production, protease expression, cytokine release and growth and differentiation factor-5 (GDF-5) receptor expression in human OA chondrocytes was evaluated in a monolayer. Afterwards, the same parameters, as well as the responsiveness to GDF-5, were evaluated in 3D culture at 340 and 380 mOsm. Our results revealed that increasing the medium osmolarity increased matrix production but also reduced cytokine release, type I collagen and protease expression. It was also demonstrated that at 380 mOsm, the response to GDF-5 in 3D culture was more robust than at 340 mOsm. For the first time, it was established that a decreased osmolarity plays a role in sustaining inflammation and catabolic activities in OA chondrocytes and decreases their responsiveness to GDF-5. This indicates that osmolarity is a critical aspect of OA pathobiology.

Growth differentiation factor 5 in cartilage and osteoarthritis: A possible therapeutic candidate

“…108 Interestingly, the response of chondrocytes to GDF-5 at 380 mOsm was more robust than that at 340 mOsm in 3D culture. 108 These results indicate that osmolarity is involved in OA pathogenesis at least partly by affecting cellular responsiveness to GDF-5. Nevertheless, modulating osmolarity to improve responsiveness to GDF-5 in cartilage might be very challenging for OA treatment (Figure 3).…”

“…Osmolarity has been demonstrated as a critical parameter of the OA pathobiology, and the proteoglycan loss during OA could reduce the osmolarity of joint tissue to 270 mOsm, 105,106 whereas the osmolarity of healthy cartilage ranges from 350 to 480 mOsm 107 . Mang and his colleagues found that increasing the medium osmolarity reduced cytokine release and increased matrix production 108 . Interestingly, the response of chondrocytes to GDF‐5 at 380 mOsm was more robust than that at 340 mOsm in 3D culture 108 .…”

Experimental Therapeutics for the Treatment of Osteoarthritis

“… 218 , 219 Decreased osmolarity contributes to sustained inflammation and catabolic activities in OA chondrocytes and impairs their responsiveness to the growth and differentiation factor (GDF)-5. This suggests that osmolarity represents a critical factor in OA pathogenesis 220 and should be further addressed. HA is often combined with other therapeutical agents, 221 eg, cells 222 or chemokines.…”

Cell-free fat extract attenuates osteoarthritis via chondrocytes regeneration and macrophages immunomodulation

“…Osteoarthritis (OA) is a common degenerative disorder characterized by the gradual degradation of articular cartilage, synovial inflammation, and remodeling of the subchondral bone [1,2]. The physiological symptoms of OA mainly include pain, joint stiffness, and reduced motion, all of which significantly affect the quality of life of the patient [3][4][5]. However, current therapies for OA include nonsurgical management (e.g., weight reduction, exercises) and pharmacological interventions such as nonsteroidal anti-inflammatory drugs and paracetamol, which only temporarily alleviate clinical symptoms rather than repairing the tissues lesions or inhibiting the progression of OA [6][7][8].…”