Distinct role of Klotho in long bone and craniofacial bone: skeletal development, repair and regeneration

Bone defects are highly prevalent diseases caused by trauma, tumors, inflammation, congenital malformations and endocrine abnormalities. Ideally effective and side effect free approach to dealing with bone defects remains a clinical conundrum. Klotho is an important protein, which plays an essential role in regulating aging and mineral ion homeostasis. More recently, research revealed the function of Klotho in regulating skeleton development and regeneration. Klotho has been identified in mesenchymal stem cells, osteoblasts, osteocytes and osteoclasts in different skeleton regions. The specific function and regulatory mechanisms of Klotho in long bone and craniofacial bone vary due to their different embryonic development, ossification and cell types, which remain unclear and without conclusion. Moreover, studies have confirmed that Klotho is a multifunctional protein that can inhibit inflammation, resist cancer and regulate the endocrine system, which may further accentuate the potential of Klotho to be the ideal molecule in inducing bone restoration clinically. Besides, as an endogenous protein, Klotho has a promising potential for clinical therapy without side effects. In the current review, we summarized the specific function of Klotho in long bone and craniofacial skeleton from phenotype to cellular alternation and signaling pathway. Moreover, we illustrated the possible future clinical application for Klotho. Further research on Klotho might help to solve the existing clinical difficulties in bone healing and increase the life quality of patients with bone injury and the elderly.