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Abstract
Based on our findings that PHD2 is a negative regulator of chondrocyte differentiation and that hypoxia signaling is implicated in the pathogenesis of osteoarthritis, we investigated the consequence of disruption of the Phd2 gene in chondrocytes on the articular cartilage phenotype in mice. Immunohistochemistry detected high expression of PHD2 in the superficial zone (SZ), while PHD3 and HIF-1α (target of PHD2) are mainly expressed in the middle-deep zone (MDZ). Conditional deletion of the Phd2 gene (cKO) in chondrocytes accelerated the transition of progenitors to hypertrophic (differentiating) chondrocytes as revealed by reduced SZ thickness, and increased MDZ thickness, as well as increased chondrocyte hypertrophy. Immunohistochemistry further revealed decreased levels of progenitor markers but increased levels of hypertrophy markers in the articular cartilage of the cKO mice. Treatment of primary articular chondrocytes, in vitro, with IOX2, a specific inhibitor of PHD2, promoted articular chondrocyte differentiation. Knockdown of Hif-1α expression in primary articular chondrocytes using lentiviral vectors containing Hif-1α shRNA resulted in reduced expression levels of Vegf, Glut1, Pgk1, and Col10 compared to control shRNA. We conclude that Phd2 is a key regulator of articular cartilage development that acts by inhibiting the differentiation of articular cartilage progenitors via modulating HIF-1α signaling.
Highlights
The articular cartilage is composed of several chondrocyte layers with unique cellular arrangements including a superficial zone (SZ), a middle zone, a deep zone, and a calcified cartilage zone
The predominant expression of Phd[3] and Hif-1α in middle-deep zone (MDZ) implicates their role in articular chondrocyte differentiation
We found that the joint space was increased by 44% (P < 0.05), and the Osteoarthritis Research Society International (OARSI) score was increased by 270% (P < 0.01) in the conditional knockout (cKO) mice compared to control mice (Fig. 3F,G), suggesting that a lack of Phd[2] may increase the risk of osteoarthritis development
Summary
The articular cartilage is composed of several chondrocyte layers with unique cellular arrangements including a superficial zone (SZ), a middle zone, a deep zone, and a calcified cartilage zone. Prolyl Hydroxylase Domain-containing Proteins (PHDs) are negative regulators of the hypoxia-inducible factors (HIFs) which moderate chondrocyte differentiation[13,14,15]. We found that deletion of Phd[2] in chondrocytes caused accelerated chondrocyte differentiation and increased endochondral bone formation in the metaphyses and epiphyses of long bones[13,14]. These data clearly demonstrate that Phd[2] negatively regulates chondrocyte differentiation and endochondral bone formation through the PHD/HIF regulatory pathway. Since articular cartilage richly contains Type II collagen (Col2), we used Col2α1-Cre line to conditionally delete Phd[2] gene in articular chondrocytes
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