Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Abstract

Objective. Parathyroid hormone 1-34 (PTH[1-34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone-related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1-34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA).Methods. We studied the effect of PTH(1-34) on human articular chondrocytes with azacytidine (azaC)-induced terminal differentiation in vitro and on papaininduced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees.Results. AzaC induced terminal differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3-10 days of treatment with 10 nM PTH(1-34). SOX9 expression was not changed by either azaC or PTH(1-34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1-34) treatment did not reverse this effect. Furthermore, PTH(1-34) treatment reversed papaininduced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats.Conclusion. Our findings indicate that PTH(1-34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.

Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells

“…This leads to the activation of protein kinase A and its downstream signalling. PTH is also known to activate phospholipase Cβ via Gαq, leading to the formation of diacylglycerol and 1,4,5-inositol triphosphate (IP3) with the subsequent activation of protein kinase C (Civitelli et al, 1988;Babich et al, 1991) and increased intracellular free Ca 2+ (Reid et al, 1987). PTH can also elevate intracellular Ca 2+ levels by stimulating the influx of extracellular Ca 2+ (Swarthout et al, 2002).…”

Protective effect of controlled release of cytokine response modifier A from chitosan microspheres on rat chondrocytes from interleukin-1β induced inflammation and apoptosis

“…The activation of caspase-3 is the most important pathway during the apoptotic process, which then induces hydrolysis of nucleic acids and cytoskeletal proteins (28,29). During apoptotic cell death, activated effector caspases cleave multiple cellular substrates, including the DNA repair enzyme PARP in chondrocytes (30).…”

Un contexte familial de défaut primaire d’éruption (DPE): identification d’une nouvelle mutation du gène PTHR-1. Cas clinique et revue de littérature

“…et leur association avec l'ostéoarthrite, ils ont évalué l'expression du PTHR-1 en comparant plusieurs versions de souris [23,24].…”

“…D'autres études chez des souris soutiennent également le rôle important de la PTHrP et de la PTHR-1 dans le développement du squelette et leur association avec l'ostéoarthrite [23,24], il serait intéressant que des études de plus grande cohorte portent sur le lien de causalité entre PTHR-1 et l'ostéoarthrite. Aussi peut-on se poser la question de l'intérêt d'un bilan squelettique plus exhaustif chez les patients atteints de DPE en tant que pathologie susceptible d'induire une ostéoarthrite.…”