HtrA1 (High temperature requirement A1) family proteins include four members, widely conserved from prokaryotes to eukaryotes, named HtrA1, HtrA2, HtrA3 and HtrA4. HtrA1 is a serine protease involved in a variety of biological functions regulating many signaling pathways degrading specific components and playing key roles in many human diseases such as neurodegenerative disorders, pregnancy complications and cancer.

Due to its role in the breakdown of many ExtraCellular Matrix (ECM) components of articular cartilage such as fibronectin, decorin and aggrecan, HtrA1 encouraged many researches on studying its role in several skeletal diseases (SDs). These studies were further inspired by the fact that HtrA1 is able to regulate the signaling of one of the most important cytokines involved in SDs, the TGFβ-1.

This review aims to summarize the data currently available on the role of HtrA1 in skeletal diseases such as Osteoporosis, Rheumatoid Arthritis, Osteoarthritis and Intervertebral Disc Degeneration (IDD). The use of HtrA1 as a marker of frailty in geriatric medicine would represent a powerful tool for identifying older individuals at risk of developing skeletal disorders, evaluating an appropriate intervention to improve quality care in these people avoiding or improving age-related SDs in the elderly population.