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Marchand-Adam et al. Rare Dis Orphan Drugs J 2023;2:3 https://dx.doi.org/10.20517/rdodj.2022.24 Page 7 of 11

Figure 3. Dysregulation of mammalian target of rapamycin (mTOR) C1 signaling in LAM pathogenesis. Constitutive activation of the
Raptor-containing mTOR leads to dysregulated mTOR signaling pathways in LAM cells. Consequently, cell proliferation, cell growth,
lung remodeling as well apoptosis and cell survival are altered. This scheme corresponds to a non-exhaustive summary, emphasizing
some key proteins which are specifically linked to mTOR-dependent under-expression or over-expression in LAM cells. Representative
upregulated molecules: HIF-1α (hypoxia-inducible factor 1α), VEGF (vascular endothelial growth factor)-C and VEGF-D, MMP (matrix
metalloproteinase), IMPDH (inosine 5'-monophosphate dehydrogenase), p70S6K (70 kDa ribosomal protein S6 kinase), SREBP (sterol
regulatory element-binding protein) and downregulated molecules: BCL2 (B-cell lymphoma 2), pTFEB (phosphorylated form of
transcription factor EB), ULK1 (Unc-51-like autophagy-activating kinase 1).

damage . A gene expression profiling analysis was performed in whole lung tissue. The authors showed
[60]
that CatK gene expression was 40-fold overexpressed in LAM compared with control lung tissue, while
immunohistochemistry confirmed overexpression of CatK protein in LAM tissue. Consistently, CatK
immunoreactivity is predominantly co-localized with LAM-associated fibroblasts in lung nodules. Also,
CatK is overexpressed in renal angiomyolipomas found in LAM, which relate to “perivascular epithelioid
cell lesions” (PECome) . Recently, the sensitivity of both CatK and HMB-45 were compared as potent
[61]
diagnostic markers for pulmonary LAM. The percentage of LAM cells expressing CatK was significantly
higher than for HMB45 and overall expression was significantly higher, confirming that CatK is a more
sensitive immunohistochemical marker than HMB45 in diagnosing pulmonary LAM .
[62]
CATHEPSIN K: AN ADDITIONAL THERAPEUTIC TARGET IN
LYMPHANGIOLEIOMYOMATOSIS?
C4-S binding is mandatory to promote the collagenolytic activity of CatK, as stated before (paragraph 1.2).
C4-S is predominantly expressed in bone and cartilage, but is also found throughout the body and
contributes to ECM remodeling processes in numerous chronic inflammatory diseases . Although the
[63]
expression level of C4-S is currently not known in LAM, the total amount of GAG is increased in lung
diseases, including idiopathic pulmonary fibrosis (IPF) or mucopolysaccharidosis (MPS), another rare
disease [63,64] . Alongside its immunoreactivity, active CatK was detected in LAM-associated fibroblasts. Also,
active secreted CatK was found in extracellular medium under in vitro conditions. It is well established that
+
monocyte-derived macrophages acidify their pericellular environment via vacuolar-type H -ATPases, thus
[21]
enabling them to maintain cysteine cathepsins, including CatK, in their active form . Similar extracellular
acidification may exist within LAM nodules, because of both expression of membrane transporters
(carbonic anhydrases, monocarboxylate transporters and sodium-bicarbonate co-transporters) and mTOR
dysregulation, which induces a metabolic dependence on aerobic glycolysis (Warburg effect). Acidification
paralleled CatK activity, and both were forcefully compromised by sodium bicarbonate co-transporter