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Figure 2. Selective inhibition of the collagenolytic activity of cathepsin K by targeting its exosite. Schematic drawing summarizing the
overall strategy to target cathepsin K by exosite-binding inhibitors.

Bourneville’s disease) [43,44] . The prevalence of the sporadic form is estimated to be 3.4-7.8/million adult
women with an incidence of 0.23 to 0.31/million women/year . In France, 320 cases of patients with LAM
[45]
were recorded in April 2021(RE-LAM-CE: National Register of Lymphangioleiomyomatosis). It is more
common in people with tuberous sclerosis, up to 30%. This pathology affects almost exclusively women in
the period of genital activity, with a median age of 35 years at the time of diagnosis. LAM is considered as a
slowly progressive neoplastic disease, responsible for the proliferation of cells derived from smooth muscle
cells in the lymphatic pathways, particularly in the lungs, resulting in progressive cystic lung destruction
responsible for the deterioration of respiratory function . The clinic is mainly marked by recurrent
[46]
pneumothorax, progressively worsening dyspnea on exertion, then chronic obstructive respiratory failure.
The respiratory function (i.e., Forced Expiratory Volume in the first second (FEV1) and Diffusing Capacity
of the lung for carbon monoxide (DLCO) is correlated with chest Computed Tomography (CT) and
histopathological abnormalities. In addition, renal angiomyolipoma injuries are observed, which can
sometimes be responsible for fatal hemorrhagic events. Since the risk is correlated with the size of the
tumors, regular monitoring is therefore required .
[47]

Diagnosis and LAM markers
Definitive diagnosis is based on tissue (most often lung) biopsy and/or the association of a clinical picture
and a characteristic chest CT appearance. Histopathological diagnosis is based on the association of cystic
cavities and disseminated proliferation of abnormal/ immature smooth muscle cells (LAM cells). LAM cells
[46]
express smooth muscle α-actin (α-SMA), desmin, vimentin and hormone receptors for estrogen and
progesterone . Moreover, LAM cells are characterized by their reactivity with mouse monoclonal antibody
[48]
HMB45 (i.e., Human Melanoma Black), which was originally developed against human melanoma and is
[49]
[50]
currently used as a diagnostic marker of LAM . The origin of these cells is still unknown, and the main