Macica Carolyn, Liang Guoying, Nasiri Ali, Broadus Arthur E
Yale University School of Medicine, New Haven, Connecticut, USA.
Arthritis Rheum. 2011 Nov;63(11):3333-43. doi: 10.1002/art.30515.
Parathyroid hormone-related protein (PTHrP) regulates the rate of differentiation of growth chondrocytes and is also expressed in articular chondrocytes. This study tested the hypothesis that PTHrP might have a regulatory role in articular chondrocyte maintenance.
Control sequences of growth differentiation factor 5 were used to delete PTHrP from articular chondrocytes in the mid-region of mouse articular cartilage. Mice with conditional deletion of PTHrP (knockout [KO]) and littermate control mice were evaluated for degenerative changes using both a time-course design and destabilization of the medial meniscus (DMM) technique. A total histologic score of degenerative changes was determined for the femoral and tibial articular surfaces (total maximum score of 60).
The time-course study revealed degenerative changes in only a minority of the KO mice. In the DMM model, male KO mice were highly susceptible to DMM-induced degenerative changes (mean ± SEM total histologic score 45 ± 2.7 in KO mice versus 23 ± 1.4 in controls; P < 0.0001 by Mann-Whitney U test), with virtually no overlap between groups. PTHrP normally functions in a feedback loop with Indian hedgehog (IHH), in which a reduction in one signaling partner induces a compensatory increase in the other. A number of phenotypic and functional markers were documented in KO mice to suggest that the IHH-PTHrP axis is capable of compensating in response to a partial Cre-driven PTHrP deletion, a finding that underscores the need to subject the mouse articular cartilage to a destabilizing challenge in order to elicit frankly degenerative findings.
PTHrP may regulate articular chondrocyte maintenance in mice.
甲状旁腺激素相关蛋白（PTHrP）调节生长软骨细胞的分化速率，并且也在关节软骨细胞中表达。本研究检验了PTHrP可能在关节软骨细胞维持中具有调节作用这一假说。
利用生长分化因子5的对照序列从小鼠关节软骨中部区域的关节软骨细胞中删除PTHrP。使用时间进程设计和内侧半月板失稳（DMM）技术对条件性删除PTHrP的小鼠（基因敲除[KO]）和同窝对照小鼠的退变变化进行评估。确定股骨和胫骨关节表面退变变化的总组织学评分（总最高分60分）。
时间进程研究显示只有少数KO小鼠出现退变变化。在DMM模型中，雄性KO小鼠对DMM诱导的退变变化高度敏感（KO小鼠的平均±标准误总组织学评分为45±2.7，而对照组为23±1.4；通过曼-惠特尼U检验，P<0.0001），两组之间几乎没有重叠。PTHrP通常在与印度刺猬因子（IHH）的反馈回路中发挥作用，其中一个信号伴侣的减少会诱导另一个信号伴侣的代偿性增加。在KO小鼠中记录了许多表型和功能标志物，表明IHH-PTHrP轴能够对部分Cre驱动的PTHrP缺失做出代偿反应，这一发现强调了需要对小鼠关节软骨施加失稳挑战以引发明显的退变表现。
PTHrP可能调节小鼠关节软骨细胞的维持。
