Inhibitory function of parathyroid hormone-related protein on chondrocyte hypertrophy: the implication for articular cartilage repair

Abstract

Cartilage repair tissue is usually accompanied by chondrocyte hypertrophy and osseous overgrowths, and a role for parathyroid hormone-related protein (PTHrP) in inhibiting chondrocytes from hypertrophic differentiation during the process of endochondral ossification has been demonstrated. However, application of PTHrP in cartilage repair has not been extensively considered. This review systemically summarizes for the first time the inhibitory function of PTHrP on chondrocyte hypertrophy in articular cartilage and during the process of endochondral ossification, as well as the process of mesenchymal stem cell chondrogenic differentiation. Based on the literature review, the strategy of using PTHrP for articular cartilage repair is suggested, which is instructive for clinical treatment of cartilage injuries as well as osteoarthritis.

Figure 1

Hypertrophic chondrocytes in normal cartilage of murine knee joint. Microphotographs showing safranin O stained sections. (A,B) Hypertrophic chondrocytes in growth plate cartilage. Boxed area in (A) indicates the region shown in (B). (C,D) Hypertrophic chondrocytes in articular cartilage. Boxed area in (C) indicates the region shown in (D). Note the sites of normal hypertrophic chondrocytes (arrows). Scale bars: 500 μm (A,C); 50 μm (B,D).

Figure 2

Hypertrophic chondrocytes in cartilage repair tissue of rabbit knee joint. Microphotograph showing collagen type × immunostained sections. (A,B) Cartilage repair tissue of osteochondral defect evaluated 16 weeks post-injury. Boxed area in (A) indicates the region shown in (B). (C,D) Normal articular cartilage. Boxed area in (C) indicates the region shown in (D). It is obvious that the chondrocytes undergo abnormal hypertrophic differentiation in cartilage repair tissue. Note the sites of abnormal hypertrophic chondrocytes (arrows). Scale bars: 50 μm (A,C); 20 μm (B,D).

Figure 3

PTHrP signaling pathways during endochondral ossification. (A) Indian hedgehog (Ihh)-parathyroid hormone-related protein (PTHrP) signaling pathway during endochondral ossification. Ihh (secreted by prehypertrophic chondrocytes) stimulates PTHrP production (synthesized by proliferating chondrocytes) (a), which in turn accelerates the proliferation of periarticular chondrocytes (b) and prevents chondrocyte hypertrophy (c). In addition, Ihh could stimulate periarticular chondrocyte differentiation independent of PTHrP (d). The detailed mechanisms indicated by the red dashed box is illustrated in (B). (B) Overview of the pathways whereby PTHrP inhibits chondrocyte hypertrophy during endochondral ossification. CDK, cyclin-dependent kinase; HDAC4, histone deacetylase 4; IGF, insulin-like growth factor; MAPK, mitogen-activated protein kinase; PK, protein kinase; PP2A, protein phosphatase 2A; PTH1R, parathyroid hormone 1 receptor;.

Figure 4

Two different strategies for articular cartilage repair with PTHrP. Left: recombinant parathyroid hormone-related protein (PTHrP)/peptide can be administered directly or with the aid of biocompatible injectable scaffolds. Right: the PTHrP gene can be delivered by intra-articular injection of gene constructs, or PTHrP-transfected cells alone or combined with injectable scaffolds.