Exogenous parathyroid hormone (1–34) attenuates knee osteoarthritis in mice through activating the TGF-β/Smad signaling pathway

OBJECTIVE: Parathyroid hormone (PTH) has been reported to delay the progression of osteoarthritis (OA), while the mechanism remains unclear. The TGF-β/Smad signaling pathway plays a key role in chondrocyte regulation and OA development. We aimed to explore the effect and mechanism of PTH on knee OA (KOA) in mice. METHODS: Anterior cruciate ligament transection (ACLT) was performed in 40 mice to induce KOA. They were randomly divided into the ACLT + PTH and ACLT + vehicle groups. Another 20 mice that underwent only arthrotomy and normal saline were allocated to the sham-vehicle group. The knee phenotypes were analyzed using radiograph, micro-CT, and histology. The mRNA and protein expression levels of related factors were detected by immunohistochemistry and qRT-PCR. RESULTS: PTH (1-34) attenuated knee OA phenotypes induced by ACLT, including reducing the modified Mankin's scores (p = 0.002, 0.001) and OARSI scores (p = 0.06, 0.02), enhancing type II collagen synthesis (p = 0.001, p < 0.001), and inhibiting type X collagen (p = 0.014, 0.011) and MMP-13 expression (p = 0.002, p < 0.001) in articular cartilage of ACLT mice at 2 weeks and 4 weeks. PTH also significantly increased the percentage of parathyroid hormone receptor 1 (PTH1R) (p < 0.001), p-cAMP response element binding protein (p-CREB) (p < 0.001), proliferating cell nuclear antigen (PCNA) (p = 0.011, p < 0.001), TGF-β receptor I (TβRI) (p = 0.002, p < 0.001), TβRII (p < 0.001), Smad2 (p = 0.014, p < 0.001), and p-Smad2/3 positive cells (p < 0.001) in the articular cartilage of ACLT mice. PTH significantly increased mRNA expression levels of PTH1R, p-CREB, PCNA, TβRI, TβRII, and Smad2 in the articular cartilage of ACLT mice (p < 0.001). CONCLUSION: PTH (1-34) attentuates knee OA induced by ACLT by stimulating proliferation, inhibiting hypertrophy and maturation of chondrocytes and the degradation of articular cartilage, and activating the TGF-β/Smad signaling pathway.