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.