An innate protector of ageing cartilage: FSTL3

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Summary During life, cartilage tissues must serve two very contrasting, almost contradictory roles. During early life, cartilage tissues facilitate increases in the length of long bone and, thus function as a transient tissue in which the resident cells, named chondrocytes, have very high rates of growth. This could hardly contrast more with the role cartilage must serve in adult joints, where it has a permanent, lifetime role in protecting joints from any possible friction and damage during movement. This permanent function is intimately coupled to very low, if any, turnover of resident chondrocytes. Ageing predisposes to an inevitable loss of cartilage that results in osteoarthritis; one of the most common ageing-related disorders. This crippling, painful and debilitating disorder has dramatic affects on the quality of life and is the leading cause of chronic disability in the US - affecting nearly 27 million people (together with 8 million in the UK). It is also the most common joint disease in cats, dogs and horses. Cartilage damage and loss is also a feature of sports injury and degeneration caused by repetitive wear and tear, particularly in the obese. Conventional treatment generally only treats the painful symptoms, so effective therapeutic interventions are desperately needed. It has been known for some time, however, that chondrocytes in adult osteoarthritic cartilage from patients and animals re-display the high rates of growth normally characteristic of early life, and that this is intimately linked to disease progression. Our pilot studies have found that a natural cell product (follistatin-like 3, FSTL3), known to regulate cell turnover in other adult tissues, might normally protect against age-related onset of OA by limiting chondrocyte growth. If this were the case, one might expect that deficiency in FSTL3 would be deleterious to the long-term, permanent function of cartilage. Our preliminary data in genetically modified mice lacking FSTL3 have shown a loss of cartilage in the joints of adults which develop an OA-like syndrome very rapidly. Thus, the FSTL3 'brake function' on chondrocyte growth will not be apparent during early life, when increased turnover is absolutely necessary, but only becomes apparent in the adult when growth has slowed. Loss of FSTL3, therefore, only impacts on cartilage integrity in the adult during ageing. These data prompt us to hypothesise: that that FSTL3 restrains chondrocyte turnover to maintain normal adult cartilage and prevent its progressive loss during ageing. To further investigate the mechanisms by which FSTL3 protects against cartilage loss and helps to maintain cartilage upon ageing we propose the following experiments in this research proposal. We will first identify when the first signs of cartilage loss are seen in FSTL3 KO mice and whether this is exacerbated when the knee cartilage is experimentally damaged, as it might be by sporting-type injury in life. We will then investigate whether the lack of FSTL3 increases the rate at which chondrocytes, multiply and die and which genes FSTL3 may influence to achieve this cartilage protection. Our research will, therefore identify how FSTL3 regulate chondrocyte behaviour and how it acts as an innate protector of cartilage loss during ageing. Finally, we will make new genetic mouse mutants that will allow us to establish if FSTL3 achieves this protection through its expression solely in cartilage and therefore whether this makes FSTL3 a good selective target for therapy. Greater appreciation of how chondrocyte growth is controlled will offer routes towards treatment for problems both of cartilage degeneration in disease and ageing and of damage in injury. Hence, the contributions from this work to our understanding of the processes underlying cartilage integrity may support development of preventative and therapeutic approaches to dealing more effectively with major and debilitating illnesses.