Pfizer, 200 CambridgePark Drive, Cambridge, MA 02140, USA.
Curr Drug Targets. 2010 May;11(5):614-9. doi: 10.2174/138945010791011884.
Therapeutic alleviation of the pathophysiology of osteoarthritis (OA) is a great and unmet medical challenge. At the basic science level, significant progress has facilitated the identification of distinct pathways and targets which appear to be central to the OA-associated deterioration of articular cartilage. For example, the dysregulated activities of aggrecanases such as ADAMTS-4 and ADAMTS-5, and collagenases such as MMP-13, point to strategies for the development of selective protease inhibitors to curtail OA disease progression. Likewise, blockade of disease-associated "pro-catabolic" cytokines may offer promising opportunities in this regard. Other novel biotherapeutic approaches are also emerging, including the use of recombinant lubricin molecules for intraarticular supplementation. Expression profiling of cartilage (and other joint tissues) to identify OA-associated genes continues to yield new potential therapeutic options, including the 'upstream' targeting of key intracellular regulators. Moving forward into the clinic, the critical evaluation and optimization of modalities for therapeutic delivery, as well as the availability and utility of appropriate disease biomarkers and ability to determine relevant patient populations, will be other important considerations in directing the advancement of novel OA therapies.
治疗缓解骨关节炎（OA）的病理生理学是一个巨大且未满足的医学挑战。在基础科学层面，重大进展促进了对特定途径和靶点的识别，这些途径和靶点似乎是关节软骨与 OA 相关退化的核心。例如，聚集素酶（如 ADAMTS-4 和 ADAMTS-5）和胶原酶（如 MMP-13）的失调活性表明，开发选择性蛋白酶抑制剂以遏制 OA 疾病进展的策略具有重要意义。同样，阻断与疾病相关的“促分解代谢”细胞因子在这方面可能提供有希望的机会。其他新的生物治疗方法也在出现，包括使用重组润滑素分子进行关节内补充。对软骨（和其他关节组织）进行表达谱分析以识别与 OA 相关的基因，这一过程不断产生新的潜在治疗选择，包括针对关键细胞内调节剂的“上游”靶向治疗。展望未来的临床应用，治疗传递方式的关键评估和优化，以及适当疾病生物标志物的可用性和实用性，以及确定相关患者群体的能力，将是指导新型 OA 治疗进展的其他重要考虑因素。
